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If you require further information please refer to the full Method Sheet PDF under the given link, or contact your local Roche country representative." }, "Chapters": [ { "Name": "IntendedUse", "Value": "

Intended use

In vitro test for the quantitative determination of total mycophenolic acid in serum or plasma as an aid in the management of mycophenolic acid therapy in renal and cardiac transplant patients on COBAS INTEGRA systems.

", "Language": "en" }, { "Name": "TestPrinciple", "Value": "

Test principle

The Roche Total MPA assay is a two-reagent system containing IMP (inosine monophosphate), NAD (nicotinamide adenine dinucleotide), and a mutant IMPDH II (inosine monophosphate dehydrogenase) enzyme. The reagents used to measure MPA concentrations in serum or plasma mimic the in vivo mechanism of the enzyme. In vivo, IMPDH II combines with IMP and NAD to form a complex. The NAD is reduced to form NADH, and IMP is converted to XMP. The NADH leaves the enzyme first. When MPA is present, the XMP is not released from the enzyme.

In the Roche Total MPA assay, a fixed amount of mutant IMPDH in the reagent combines with fixed amounts of IMP and NAD in the reagents. The formation of NADH is measured at 340 nm. When MPA is present in the serum or plasma sample, the formation of NADH by the reagents is inhibited, as measured by a decrease in the signal at 340 nm. MPA concentration is inversely proportional to the rate of NADH formation. The reaction has been optimized for a non-linear, 6‑point calibration.

", "Language": "en" }, { "Name": "MeasuringRange", "Value": "

Limits and ranges

Measuring range

0.4‑15 µg/mL (1.2‑46.8 µmol/L)

Manually dilute samples above the measuring range with the diluent (equivalent to the 0 µg/mL calibrator) from the Roche Total MPA Calibrators (1 part sample + 4 parts diluent) and reassay. Multiply the result by 5 to obtain the specimen value.

Lower limits of measurement

Lower detection limit of the test:

0.3 µg/mL (0.9 µmol/L)

The lower detection limit represents the lowest measurable analyte level that can be distinguished from zero. It is calculated as the value lying 2 standard deviations above that of the 0 µg/mL calibrator (standard A + 2 SD, repeatability, n = 21).

Functional sensitivity:

0.4 µg/mL (1.2 µmol/L)

The functional sensitivity is calculated as the lowest concentration from clinical samples with a CV of ≤ 20 %, tested in triplicate over 10 days (n = 30).

", "Language": "en" }, { "Name": "ExpectedValues", "Value": "

Expected values

The therapeutic range of mycophenolic acid is not yet fully established and is dependent on transplant type and coadministered drugs. Optimal mycophenolic acid assay values to prevent organ rejection may vary based on the test system and therefore should be established for each test system. Laboratories should include identification of the assay or method used in order to aid in interpretation of the results.

Optimal ranges depend on the patient’s clinical state, coadministration of other immunosuppressants, time post-transplant, and a number of other factors. Therefore, individual MPA values cannot be used as the sole indicator for making changes in treatment regimen, and each patient should be thoroughly evaluated clinically before changes in treatment regimens are made.

Decreased incidences of rejection in the early months post-transplantation have been reported in renal transplant patients with predose MPA concentrations (measured by HPLC) of ≥ 1.3 µg/mL with coadministration of cyclosporine and ≥ 1.9 µg/mL with coadministration of tacrolimus.

LREFVan Gelder T, Meur YL, Shaw LM, et al. Therapeutic drug monitoring of mycophenolate mofetil in transplantation. Ther Drug Monit 2006;28(2):145-154.
,
LREFCox VC, Ensom MHH. Mycophenolate mofetil for solid organ transplantation: Does the evidence support the need for clinical pharmacokinetic monitoring? Ther Drug Monit 2003;25(2):137-157.
An upper therapeutic range based on development of toxicity has not been established. The clinical ramifications of MPA concentrations beyond the early post transplantation periods are not yet known.
LREFVan Gelder T, Meur YL, Shaw LM, et al. Therapeutic drug monitoring of mycophenolate mofetil in transplantation. Ther Drug Monit 2006;28(2):145-154.

In cardiac transplant patients, predose MPA concentrations (measured by HPLC) of 1.2‑3.5 µg/mL have been recommended to minimize incidences of rejection.

LREFMeiser BM. Therapeutic drug monitoring of mycophenolic acid in cardiac tranplant recipients: does it make sense? Curr Opin Organ Transplant 2005;10:350-354.
,
LREFVan Gelder T, Meur YL, Shaw LM, et al. Therapeutic drug monitoring of mycophenolate mofetil in transplantation. Ther Drug Monit 2006;28(2):145-154.
Higher pre-dose concentrations (≥ 2.5 µg/mL) in the early post-transplantation period (< 6 months) have also been suggested.
LREFMeiser BM. Therapeutic drug monitoring of mycophenolic acid in cardiac tranplant recipients: does it make sense? Curr Opin Organ Transplant 2005;10:350-354.
,
LREFGajarski RJ, Crowley DC, Zamberlan MC, et al. Lack of correlation between MMF dose and MPA level in pediatric and young adult cardiac transplant patients: Does the MPA level matter? Am J Transplant 2004;4:1495-1500.
,
LREFMeiser BM, Reichart B. New agents and new strategies in immunosuppression after heart transplantation. Curr Opin Organ Transplant 2002;7:226-232.
Pediatric cardiac transplant patients have been shown to require higher doses of MPA in comparison to adults due to differences in MPA metabolism.
LREFMeiser BM. Therapeutic drug monitoring of mycophenolic acid in cardiac tranplant recipients: does it make sense? Curr Opin Organ Transplant 2005;10:350-354.
,
LREFGajarski RJ, Crowley DC, Zamberlan MC, et al. Lack of correlation between MMF dose and MPA level in pediatric and young adult cardiac transplant patients: Does the MPA level matter? Am J Transplant 2004;4:1495-1500.
,
LREFDipchand AI, Pietra B, McCrindle BW, et al. Mycophenolic acid levels in pediatric heart transplant recipients receiving mycophenolate mofetil. J Heart Lung Transplant 2001;20(10):1035-1043.

Each laboratory should investigate the transferability of the expected values to its own patient population and if necessary determine its own reference ranges.

", "Language": "en" }, { "Name": "LimitationInterference", "Value": "

Limitations - interference

See the Analytical specificity section of this method sheet for information on substances tested for cross-reactivity in this assay. There is the possibility that other substances and/or factors may interfere with the test and cause erroneous results (e.g. technical or procedural errors). Specimens with assay values greater than the highest calibrator will be flagged by the system and must be repeated after appropriate dilution of the original sample with the zero calibrator or with the diluent from the Total MPA Calibrator kit.

Criterion: Recovery within ± 10 % of initial value at MPA concentrations of approximately 1‑5 µg/mL (3.12‑15.6 µmol/L) and 8‑12 µg/mL (25.0‑37.5 µmol/L).

Icterus:

LREFGlick MR, Ryder KW, Jackson SA. Graphical Comparisons of Interferences in Clinical Chemistry Instrumentation. Clin Chem 1986;32:470-475.
No significant interference up to an I index of 66 for conjugated bilirubin and 17 for unconjugated bilirubin (approximate conjugated bilirubin concentration: 1129 µmol/L or 66 mg/dL; approximate unconjugated bilirubin concentration: 291 µmol/L or 17 mg/dL).

Hemolysis:

LREFGlick MR, Ryder KW, Jackson SA. Graphical Comparisons of Interferences in Clinical Chemistry Instrumentation. Clin Chem 1986;32:470-475.
No significant interference up to an H index of 1000 (approximate hemoglobin concentration: 621 µmol/L or 1000 mg/dL).

Lipemia:

LREFGlick MR, Ryder KW, Jackson SA. Graphical Comparisons of Interferences in Clinical Chemistry Instrumentation. Clin Chem 1986;32:470-475.
No significant interference up to a triglycerides level of 500 mg/dL (5.65 mmol/L) with a recovery specification of ± 10 % or 600 mg/dL (6.78 mmol/L) with a recovery specification of ± 15 %.
No significant interference up to an intralipid level of 93 mg/dL. There is poor correlation between the L index (corresponds to turbidity) and triglycerides concentration. Avoid the use of lipemic specimens.

Total protein: No significant interference from total protein concentrations of 4‑11 g/dL.

Albumin: No significant interference from albumin up to a concentration of 5.4 g/dL.

Gamma globulin: No significant interference from gamma globulin up to a concentration of 6.2 g/dL.

Cholesterol: No significant interference from cholesterol up to a concentration of 500 mg/dL.

Creatinine: No significant interference from creatinine up to a concentration of 10 mg/dL.

Uric acid: No significant interference from uric acid up to a concentration of 20 mg/dL.

For diagnostic purposes, the results should always be assessed in conjunction with the patient’s medical history, clinical examination and other findings.

ACTION REQUIRED
Special Wash Programming: The use of special wash steps is mandatory when certain test combinations are run together on COBAS INTEGRA analyzers. Refer to the CLEAN Method Sheet for further instructions and for the latest version of the Extra wash cycle list.
Where required, special wash/carry-over evasion programming must be implemented prior to reporting results with this test.

", "Language": "en" }, { "Name": "OrderInformation", "Value": "

Orderinformation_INT

Order information

Analyzer(s) on which cobas c pack(s) can be used

04357213190

Mycophenolic Acid (100 tests)

System-ID 07 6823 5

COBAS INTEGRA 400 plus

Materials required (but not provided):

04357221190

Total MPA Calibrators
Calibrators A-F (6 × 1 × 5 mL)
Diluent (1 × 10 mL)

System-ID 07 6824 3

04357230190

Total MPA Controls
Level I (2 × 5 mL)
Level II (2 × 5 mL)
Level III (2 × 5 mL)


System-ID 07 6935 5
System-ID 07 6936 3
System-ID 07 6937 7

", "Language": "en" }, { "Name": "SystemInformation", "Value": "

System information

Test TMPA, test ID 0‑623

", "Language": "en" }, { "Name": "Handling", "Value": "

Reagent handling

Ready for use

", "Language": "en" }, { "Name": "TestDefinition", "Value": "

Application for serum and plasma

Test definition

Measuring mode

Absorbance

Abs. calculation mode

Kinetic

Reaction mode

R1/R2-S

Reaction direction

Increase

Wavelength

340/409 nm

Reading cycle blank/test

52/65

Unit

µg/mL

Pipetting parameters

Diluent (H2O)

R1

185 µL

4 µL

R2

19 µL

4 µL

Sample

3 µL

7 µL

Total volume

222 µL

", "Language": "en" }, { "Name": "StorageStability", "Value": "

Storage and stability

Shelf life at 2‑8 °C

See expiration date on cobas c pack label

On‑board in use at 10‑15 °C

12 weeks

", "Language": "en" }, { "Name": "Calibration", "Value": "

Calibration

Calibrators

Total MPA Calibrators
Bottles A-F

MPA conc.

0, 1, 3, 5, 10, 15 µg/mL

Calibration mode

Logit/log 4

Calibration replicate

Duplicate recommended

Calibration interval

Each lot, every 9 days and as required following quality control procedures

Calibration interval may be extended based on acceptable verification of calibration by the laboratory.

A calibration curve must be prepared using the Total MPA Calibrators. Calibrators must be placed from the highest concentration (F) first, to the lowest (A) last, on the CAL/QC rack. This curve is retained in memory by the COBAS INTEGRA systems and recalled for later use.

Traceability: The Total MPA Calibrators are prepared to contain known quantities of mycophenolic acid in normal human serum and are traceable to a primary reference method (HPLC).

LREFBrandhorst G, Streit F, Goetze S, et al. Quantification by liquid chromatography tandem mass spectrometry of mycophenolic acid and its phenol and acyl glucuronide metabolites. Clin Chem 2006;52:1962-1964.

", "Language": "en" }, { "Name": "Limitations", "Value": "", "Language": "en" }, { "Name": "PerformanceData", "Value": "

Specific performance data

Representative performance data on the COBAS INTEGRA analyzers are given below. Results obtained in individual laboratories may differ.

", "Language": "en" }, { "Name": "Precision", "Value": "

Precision

Precision was determined using Roche Total MPA Controls and human plasma samples in accordance with the CLSI (Clinical and Laboratory Standards Institute)guidelines.

The following results were obtained on a COBAS INTEGRA 700 analyzer with repeatability (n = 63) and intermediate precision (3 aliquots per run, 1 run per day, 21 days):

Repeatability

Mean
µg/mL (µmol/L)

SD
µg/mL (µmol/L)

CV
%

Level 1

0.93 (2.90)

0.01 (0.03)

1.1

Level 2

3.54 (11.05)

0.01 (0.03)

0.4

Level 3

12.37 (38.62)

0.06 (0.19)

0.5

HP 1*

1.61 (5.03)

0.01 (0.03)

0.8

HP 2*

6.36 (19.86)

0.04 (0.12)

0.7

Intermediate precision

Mean
µg/mL (µmol/L)

SD
µg/mL (µmol/L)

CV
%

Level 1

0.93 (2.90)

0.04 (0.12)

4.5

Level 2

3.54 (11.05)

0.06 (0.19)

1.8

Level 3

12.37 (38.62)

0.16 (0.50)

1.3

HP 1*

1.61 (5.03)

0.04 (0.12)

2.2

HP 2*

6.36 (19.86)

0.11 (0.34)

1.8

*HP 1 and HP 2 are non-spiked pooled clinical samples.

The following results were obtained on a COBAS INTEGRA 400 analyzer with repeatability (n = 30) and intermediate precision (3 aliquots per run, 1 run per day, 10 days):

Repeatability

Mean
µg/mL (µmol/L)

SD
µg/mL (µmol/L)

CV
%

Level 1

0.91 (2.84)

0.02 (0.06)

2.0

Level 2

3.48 (10.86)

0.04 (0.12)

1.1

Level 3

12.22 (38.15)

0.03 (0.09)

0.3

HP 1**

1.55 (4.84)

0.03 (0.09)

1.7

HP 2**

9.11 (28.44)

0.07 (0.21)

0.8

Intermediate precision

Mean
µg/mL (µmol/L)

SD
µg/mL (µmol/L)

CV
%

Level 1

0.91 (2.84)

0.04 (0.12)

4.5

Level 2

3.48 (10.86)

0.06 (0.19)

1.8

Level 3

12.22 (38.15)

0.09 (0.28)

0.7

HP 1**

1.55 (4.84)

0.05 (0.16)

3.0

HP 2**

9.11 (28.44)

0.08 (0.25)

0.9

**HP 1 and HP 2 are spiked MPA plasma pools.

", "Language": "en" }, { "Name": "MethodComparison", "Value": "

Method comparison

Mycophenolic acid values for human plasma samples obtained with the Roche Total Mycophenolic Acid assay were compared to those determined with three independent validated MPA HPLC methods. Samples from renal and cardiac transplant patients were tested with the Roche Total Mycophenolic Acid assay at two external clinical sites and also internally, with concurrent HPLC testing at each site.

The trial included a total of 571 samples collected from post-transplant patients. The Passing-Bablok statistics of the correlations are shown in the table below.

LREFBablok W, Passing H, Bender R, et al. A general regression procedure for method transformation. Application of linear regression procedures for method comparison studies in clinical chemistry, Part III. J Clin Chem Clin Biochem 1988 Nov;26(11):783-790.
Samples tested on the COBAS INTEGRA 800 analyzer were obtained from an international trial of renal transplant recipients (147 samples from 86 adult patients). Demographics for the other sites are subsequently described with the representative regression plots that follow the table.

Methodology vs. HPLC

Slope
(95 % CI)

Intercept
(95 % CI)

Correlation Coefficient

Sample Size

Sample Range
(µg/mL)

COBAS INTEGRA 700 analyzer

Renal

1.062

(1.044-1.079)

0.019

(-0.021-0.073)

0.997

89

0.46-13.6

Cardiac

1.088

(1.050-1.125)

-0.028

(-0.110-0.045)

0.993

70

0.57-14.2

Combined

1.068

(1.052-1.085)

0.005

(-0.029-0.050)

0.995

159

0.46-14.2

COBAS INTEGRA 400 plus analyzer

Renal

1.010

(0.988-1.035)

0.068

(0.034-0.105)

0.995

148

0.4-14.8

Cardiac

1.014

(0.996-1.031)

0.057

(-0.004-0.103)

0.992

117

0.4-13.6

Combined

1.011

(1.000-1.025)

0.064

(0.038-0.090)

0.993

265

0.4-14.8

COBAS INTEGRA 800 analyzer

Renal

1.100

(1.073-1.120)

-0.120

(-0.192-(-0.066))

0.994

147

0.5-14.7

The following graph shows the correlation testing of the Roche Total Mycophenolic Acid assay on the COBAS INTEGRA 700 analyzer vs HPLC. The same data sets are depicted in the Bland-Altman difference plot shown below the regression plot. The sample population for this internal study included 89 renal and 70 cardiac patients. Other demographics for this sample population are unknown. Passing-Bablok statistics for the correlation are included in the method comparison table above.

COBAS INTEGRA 700 analyzer µg/mL

Roche Total Mycophenolic Acid
(COBAS INTEGRA 700 analyzer) vs HPLC

HPLC
µg/mL

N = 159
Mean (Y-X) = 0.38
SD (Y-X) = 0.52
1.96 SD = 1.02
Mean + 1.96 SD = 1.41
Mean – 1.96 SD = -0.64

The following graph shows the correlation testing of the Roche Total Mycophenolic Acid assay on the COBAS INTEGRA 400 plus analyzer vs HPLC. The same data sets are depicted in the Bland-Altman difference plot shown below the regression plot. The sample population for this external study included 265 samples (148 renal and 117 cardiac) from a total of 209 “routine” adult transplant recipients. Passing-Bablok statistics for the correlation are included in the method comparison table above.

COBAS INTEGRA 400 plus analyzer µg/mL

Roche Total Mycophenolic Acid
(COBAS INTEGRA 400 plus analyzer) vs HPLC

HPLC
µg/mL

N = 265
Mean (Y-X) = 0.13
SD (Y-X) = 0.38
1.96 SD = 0.75
Mean + 1.96 SD = 0.881
Mean – 1.96 SD = -0.62

", "Language": "en" }, { "Name": "Summary", "Value": "

Summary

Mycophenolic acid is prescribed as mycophenolate mofetil (MMF), a morpholino ester, or as mycophenolate sodium. The MMF prodrug is rapidly metabolized to the active compound, MPA, via cleavage of the ester linkage.

LREFWeber LT, Shipkova M, Armstrong VW, et al. The pharmacokinetic-pharmacodynamic relationship for total and free mycophenolic acid in pediatric renal transplant recipients: A report of the German study group on mycophenolate mofetil therapy. J Am Soc Nephrol 2002;13:759-768.
MPA inhibits de novo purine biosynthesis by the reversible, noncompetitive inhibition of inosine monophosphate dehydrogenase (IMPDH‑II).
LREFWeber LT, Shipkova M, Armstrong VW, et al. The pharmacokinetic-pharmacodynamic relationship for total and free mycophenolic acid in pediatric renal transplant recipients: A report of the German study group on mycophenolate mofetil therapy. J Am Soc Nephrol 2002;13:759-768.
,
LREFShaw LM, Nichols A, Hale M, et al. Therapeutic monitoring of mycophenolic acid: A consensus panel report. Clin Biochem 1998;31(5):317-322.
The inhibition of IMPDH‑II in activated lymphocytes reduces intracellular guanine nucleotide pools, thus arresting lymphocyte proliferation.
LREFWu JC. Mycophenolate mofetil: molecular mechanism of action. Perspect Drug Discovery Design 1994;2:185-204.
,
LREFRansom JT. The mechanism of action of mycophenolate mofetil. Ther Drug Monit 1995;17:681-684.

MPA is metabolized in the liver by glucuronidation at the phenolic hydroxyl group to the pharmacologically inactive mycophenolic acid glucuronide (MPAG). Plasma levels of MPAG are approximately 40-fold higher than those of the parent drug.

LREFSchutz E, Shikova M, Armstrong VW, et al. Therapeutic drug monitoring of mycophenolic acid: comparison of HPLC and immunoassay reveals new metabolites. Transplant Proc 1998;30:1185-1187.
,
LREFIndjova D, Kassabova L, Svinarov D. J Chromatog B 2005;817:327-330.
In addition to the primary metabolite, two additional metabolites of MPA have been identified, the acyl glucuronide (Ac‑MPAG) and the phenolic glucoside of MPA. Of these two, only the acyl glucuronide is able to inhibit IMPDH‑II in vitro.
LREFWeber LT, Shipkova M, Armstrong VW, et al. The pharmacokinetic-pharmacodynamic relationship for total and free mycophenolic acid in pediatric renal transplant recipients: A report of the German study group on mycophenolate mofetil therapy. J Am Soc Nephrol 2002;13:759-768.

Growing clinical evidence indicates that therapeutic drug monitoring of MPA can maximize the therapeutic benefit of the drug and minimize its adverse effects.

LREFMeiser BM. Therapeutic drug monitoring of mycophenolic acid in cardiac tranplant recipients: does it make sense? Curr Opin Organ Transplant 2005;10:350-354.
,
LREFGajarski RJ, Crowley DC, Zamberlan MC, et al. Lack of correlation between MMF dose and MPA level in pediatric and young adult cardiac transplant patients: Does the MPA level matter? Am J Transplant 2004;4:1495-1500.
,
LREFDipchand AI, Pietra B, McCrindle BW, et al. Mycophenolic acid levels in pediatric heart transplant recipients receiving mycophenolate mofetil. J Heart Lung Transplant 2001;20(10):1035-1043.
,
LREFKuypers DRJ. Immunosuppressive drug monitoring- What to use in clinical practice today to improve renal graft outcome? Transplant International 2005;18:140-150.
,
LREFHessilink DA, van Gelder T. The influence of cyclosporine on mycophenolic acid plasma concentrations: A review. Transplant Rev 2003;17(3):158-163.
It is generally co-administered with calcineurin inhibitors (cyclosporine or tacrolimus) and, more recently, other immunosuppressants including sirolimus.
LREFMeiser BM. Therapeutic drug monitoring of mycophenolic acid in cardiac tranplant recipients: does it make sense? Curr Opin Organ Transplant 2005;10:350-354.
,
LREFVan Gelder T, Meur YL, Shaw LM, et al. Therapeutic drug monitoring of mycophenolate mofetil in transplantation. Ther Drug Monit 2006;28(2):145-154.

Peak levels of MPA in plasma occur approximately 1‑2 hours after oral dosing. A secondary peak then occurs 6‑12 hours after dosing due to enterohepatic recirculation of the drug. The pharmacokinetics of MPA exhibit wide between-patient variability and may be altered in specific patient populations due to concomitant disease states or interactions with other immunosuppressants.

LREFCox VC, Ensom MHH. Mycophenolate mofetil for solid organ transplantation: Does the evidence support the need for clinical pharmacokinetic monitoring? Ther Drug Monit 2003;25(2):137-157.
,
LREFShaw LM, Korecka M, Venkataramanan R, et al. Mycophenolic acid pharmacodynamics and pharmacokinetics provide a basis for rational monitoring strategies. Am J Transplant 2003;3:534-542.
,
LREFShaw LM, Holt DW, Oellerich M, et al. Current issues in therapeutic drug monitoring of mycophenolic acid: Report of a roundtable discussion. Ther Drug Monit 2001;23(4):305-315.
Cyclosporine inhibits the transport of MPAG from hepatocytes into bile, resulting in decreased enterohepatic recirculation.
LREFShaw LM, Holt DW, Oellerich M, et al. Current issues in therapeutic drug monitoring of mycophenolic acid: Report of a roundtable discussion. Ther Drug Monit 2001;23(4):305-315.
Thus, in comparison to tacrolimus coadministration, MPA plasma levels may be reduced with coadministration of cyclosporine. Due to the variability in patient plasma MPA levels, monitoring MPA levels may help to optimize outcomes in patients with high risks of organ rejection after transplantation.
LREFVan Gelder T, Meur YL, Shaw LM, et al. Therapeutic drug monitoring of mycophenolate mofetil in transplantation. Ther Drug Monit 2006;28(2):145-154.
,
LREFMeiser BM, Pfeiffer M, Schmidt D, et al. Combination therapy with tacrolimus and mycophenolate mofetil following cardiac transplantation:importance of mycophenolic acid therapeutic drug monitoring. J Heart Lung Transplant 1999;18(2):143-149.

", "Language": "en" }, { "Name": "Reagents", "Value": "

Reagents - working solutions

R1

Enzyme reagent
IMPDH‑II in buffer: 15.7 U/L; IMP: 4.8 mmol/L; stabilizer; preservative

R2

Substrate reagent
NAD: 10 mmol/L in buffer; stabilizer; preservative

R1 is in position A and R2 is in position B.

", "Language": "en" }, { "Name": "PrecautionsWarnings", "Value": "

Precautions and warnings

For in vitro diagnostic use for health care professionals. Exercise the normal precautions required for handling all laboratory reagents.

Infectious or microbial waste:
Warning: handle waste as potentially biohazardous material. Dispose of waste according to accepted laboratory instructions and procedures.

Environmental hazards:
Apply all relevant local disposal regulations to determine the safe disposal.

Safety data sheet available for professional user on request.

For USA: Caution: Federal law restricts this device to sale by or on the order of a physician.

This kit contains components classified as follows in accordance with the Regulation (EC) No. 1272/2008:

Danger

H350

May cause cancer.

Prevention:

P201

Obtain special instructions before use.

P202

Do not handle until all safety precautions have been read and understood.

P280

Wear protective gloves/ protective clothing/ eye protection/ face protection/ hearing protection.

Response:

P308 + P313

IF exposed or concerned: Get medical advice/attention.

Storage:

P405

Store locked up.

Disposal:

P501

Dispose of contents/container to an approved waste disposal plant.

EUH 208

Contains Sodium Hydroxymethylglycinate. May produce an allergic reaction.

Product safety labeling follows EU GHS guidance.

Contact phone: all countries: +49-621-7590, USA: 1-800-428-2336

", "Language": "en" }, { "Name": "Caution", "Value": "", "Language": "en" }, { "Name": "QualityControl", "Value": "

Quality control

Quality control

Total MPA Controls

Control interval

24 hours recommended

Control sequence

User defined

Control after calibration

Recommended

For quality control, use control materials as listed in the “Order information” section. In addition, other suitable control material can be used.

The control intervals and limits should be adapted to each laboratory’s individual requirements. Values obtained should fall within the defined limits. Each laboratory should establish corrective measures to be taken if values fall outside the defined limits.

Follow the applicable government regulations and local guidelines for quality control.

", "Language": "en" }, { "Name": "SpecimenPreparation", "Value": "

Specimen collection and preparation

For specimen collection and preparation only use suitable tubes or collection containers.

Only the specimens listed below were tested and found acceptable.
Serum: Collect serum using standard sampling tubes.
Plasma: K2‑ and K3‑EDTA plasma

The sample types listed were tested with a selection of sample collection tubes that were commercially available at the time of testing, i.e. not all available tubes of all manufacturers were tested. Sample collection systems from various manufacturers may contain differing materials which could affect the test results in some cases. When processing samples in primary tubes (sample collection systems), follow the instructions of the tube manufacturer.

Centrifuge samples containing precipitates before performing the assay.

See the limitations and interferences section for details about possible sample interferences.

Specimens should be tested within 8 hours of collection if kept at room temperature. If specimens must be stored for later testing, they should be kept at 2‑8 °C for up to 96 hours or at ‑20 °C or below for up to 11 months. 

LREFShaw LM, Holt DW, Oellerich M, et al. Current issues in therapeutic drug monitoring of mycophenolic acid: Report of a roundtable discussion. Ther Drug Monit 2001;23(4):305-315.
,
LREFShipkova M, Armstrong VM, Schneider T, et al. Stability of mycophenolic acid glucuronide in human plasma. Clin Chem 1999;45(1):127-129.
Specimens should not be repeatedly frozen and thawed (do not exceed 5 freeze/thaw cycles).

Invert thawed specimens several times prior to testing.

Sample stability claims were established by experimental data by the manufacturer or based on reference literature and only for the temperatures/time frames as stated in the method sheet. It is the responsibility of the individual laboratory to use all available references and/or its own studies to determine specific stability criteria for its laboratory.

", "Language": "en" } ] } }, { "ProductSpecVariant": { "MetaData": { "DocumentMaterialNumber": "0004357213190c501", "ProductName": "MPA", "ProductLongName": "Mycophenolic Acid", "Language": "en", "DocumentVersion": "11", "DocumentObjectID": "FF0000000584FC0E", "DocumentOriginID": "FF0000000068960E", "MaterialNumbers": [ "04357213190" ], "InstrumentReferences": [ { "ID": "308", "BrandName": "cobas c 311" }, { "ID": "2324", "BrandName": "cobas c 502" }, { "ID": "309", "BrandName": "cobas c 501" } ], "DisclaimerText": "Product information shown on this page contains elements of the officially released Method Sheet. If you require further information please refer to the full Method Sheet PDF under the given link, or contact your local Roche country representative." }, "Chapters": [ { "Name": "IntendedUse", "Value": "

Intended use

In vitro test for the quantitative determination of total mycophenolic acid in serum or plasma as an aid in the management of mycophenolic acid therapy in renal and cardiac transplant patients on Roche/Hitachi cobas c systems.

", "Language": "en" }, { "Name": "TestPrinciple", "Value": "

Test principle

The Roche Total MPA assay is a two‑reagent system containing IMP (inosine monophosphate), NAD (nicotinamide adenine dinucleotide), and a mutant IMPDH II (inosine monophosphate dehydrogenase) enzyme. The reagents used to measure MPA concentrations in serum or plasma mimic the in vivo mechanism of the enzyme. In vivo, IMPDH II combines with IMP and NAD to form a complex. The NAD is reduced to form NADH, and IMP is converted to XMP. The NADH leaves the enzyme first. When MPA is present, the XMP is not released from the enzyme.

In the Roche Total MPA assay, a fixed amount of mutant IMPDH in the reagent combines with fixed amounts of IMP and NAD in the reagents. The formation of NADH is measured at 340 nm. When MPA is present in the serum or plasma sample, the formation of NADH by the reagents is inhibited, as measured by a decrease in the signal at 340 nm. MPA concentration is inversely proportional to the rate of NADH formation. The reaction has been optimized for a non‑linear, six‑point calibration.

", "Language": "en" }, { "Name": "MeasuringRange", "Value": "

Limits and ranges

Measuring range

0.4‑15 µg/mL (1.2‑46.8 µmol/L)

Manually dilute samples above the measuring range with the diluent (equivalent to the 0 µg/mL calibrator) from the Roche Total MPA Calibrators (1 part sample + 4 parts diluent) and reassay. Multiply the result by 5 to obtain the specimen value.

Lower limits of measurement

Lower detection limit of the test

0.3 µg/mL (0.9 µmol/L)

The lower detection limit represents the lowest measurable analyte level that can be distinguished from zero. It is calculated as the value lying 2 standard deviations above that of the 0 µg/mL calibrator (standard A + 2 SD, repeatability, n = 21).

Functional sensitivity

0.4 µg/mL (1.2 µmol/L)

The functional sensitivity is calculated as the lowest concentration from clinical samples with a CV of ≤ 20 %, tested in triplicate over 10 days (n = 30).

", "Language": "en" }, { "Name": "ExpectedValues", "Value": "

Expected values

The therapeutic range of mycophenolic acid is not yet fully established and is dependent on transplant type and coadministered drugs. Optimal mycophenolic acid assay values to prevent rejection may vary based on the test system and therefore should be established for each test system. Laboratories should include identification of the assay or method used in order to aid in interpretation of the results.

Optimal ranges depend on the patient’s clinical state, coadministration of other immunosuppressants, time post‑transplant and a number of other factors. Therefore, individual MPA values cannot be used as the sole indicator for making changes in treatment regimen and each patient should be thoroughly evaluated clinically before changes in treatment regimens are made.

Decreased incidences of rejection in the early months post‑transplantation have been reported in renal transplant patients with predose MPA concentrations (measured by HPLC) of ≥ 1.3 µg/mL with coadministration of cyclosporine and ≥ 1.9 µg/mL with coadministration of tacrolimus.

LREFVan Gelder T, Meur YL, Shaw LM, et al. Therapeutic drug monitoring of mycophenolate mofetil in transplantation. Ther Drug Monit 2006;28(2):145-154.
,
LREFCox VC, Ensom MHH. Mycophenolate mofetil for solid organ transplantation: Does the evidence support the need for clinical pharmacokinetic monitoring? Ther Drug Monit 2003;25(2):137-157.
An upper therapeutic range based on development of toxicity has not been established. The clinical ramifications of MPA concentrations beyond the early post transplantation periods are not yet known.
LREFVan Gelder T, Meur YL, Shaw LM, et al. Therapeutic drug monitoring of mycophenolate mofetil in transplantation. Ther Drug Monit 2006;28(2):145-154.

In cardiac transplant patients, predose MPA concentrations (measured by HPLC) of 1.2‑3.5 µg/mL have been recommended to minimize incidences of rejection.

LREFMeiser BM. Therapeutic drug monitoring of mycophenolic acid in cardiac tranplant recipients: does it make sense? Curr Opin Organ Transplant 2005;10:350-354.
,
LREFVan Gelder T, Meur YL, Shaw LM, et al. Therapeutic drug monitoring of mycophenolate mofetil in transplantation. Ther Drug Monit 2006;28(2):145-154.
Higher pre‑dose concentrations (≥ 2.5 µg/mL) in the early post‑transplantation period (< 6 months) have also been suggested.
LREFMeiser BM. Therapeutic drug monitoring of mycophenolic acid in cardiac tranplant recipients: does it make sense? Curr Opin Organ Transplant 2005;10:350-354.
,
LREFGajarski RJ, Crowley DC, Zamberlan MC, et al. Lack of correlation between MMF dose and MPA level in pediatric and young adult cardiac transplant patients: Does the MPA level matter? Am J Transplant 2004;4:1495-1500.
,
LREFMeiser BM, Reichart B. New agents and new strategies in immunosuppression after heart transplantation. Curr Opin Organ Transplant 2002;7:226-232.
Pediatric cardiac transplant patients have been shown to require higher doses of MPA in comparison to adults due to differences in MPA metabolism.
LREFMeiser BM. Therapeutic drug monitoring of mycophenolic acid in cardiac tranplant recipients: does it make sense? Curr Opin Organ Transplant 2005;10:350-354.
,
LREFGajarski RJ, Crowley DC, Zamberlan MC, et al. Lack of correlation between MMF dose and MPA level in pediatric and young adult cardiac transplant patients: Does the MPA level matter? Am J Transplant 2004;4:1495-1500.
,
LREFDipchand AI, Pietra B, McCrindle BW, et al. Mycophenolic acid levels in pediatric heart transplant recipients receiving mycophenolate mofetil. J Heart Lung Transplant 2001;20(10):1035-1043.

Each laboratory should investigate the transferability of the expected values to its own patient population and if necessary determine its own reference ranges.

", "Language": "en" }, { "Name": "LimitationInterference", "Value": "

Limitations - interference

See the Analytical specificity section of this insert for information on substances tested for cross‑reactivity in this assay. There is the possibility that other substances and/or factors may interfere with the test and cause erroneous results (e.g., technical or procedural errors). Specimens with assay values greater than the highest calibrator will be flagged by the system and must be repeated after appropriate dilution of the original sample with the zero calibrator or with the diluent from the Total MPA Calibrator kit.

Criterion: Recovery within ± 10 % of initial value at MPA concentrations of approximately 1‑5 µg/mL (3.1‑15.6 µmol/L) and 8‑12 µg/mL (25.0‑37.5 µmol/L).

Serum/Plasma

Icterus:

LREFGlick MR, Ryder KW, Jackson SA. Graphical Comparisons of Interferences in Clinical Chemistry Instrumentation. Clin Chem 1986;32:470-475.
No significant interference up to an I index of 66 for conjugated bilirubin and 17 for unconjugated bilirubin (approximate conjugated bilirubin concentration: 1129 µmol/L or 66 mg/dL; approximate unconjugated bilirubin concentration: 291 µmol/L or 17 mg/dL).

Hemolysis:

LREFGlick MR, Ryder KW, Jackson SA. Graphical Comparisons of Interferences in Clinical Chemistry Instrumentation. Clin Chem 1986;32:470-475.
No significant interference up to an H index of 1000 (approximate hemoglobin concentration: 621 µmol/L or 1000 mg/dL).

Lipemia (Intralipid):

LREFGlick MR, Ryder KW, Jackson SA. Graphical Comparisons of Interferences in Clinical Chemistry Instrumentation. Clin Chem 1986;32:470-475.
No significant interference up to an L index of 93. There is poor correlation between the L index (corresponds to turbidity) and triglycerides concentration.

Avoid the use of lipemic specimens.

Triglycerides: No significant interference from triglycerides up to a concentration of 500 mg/dL (5.65 mmol/L) with a recovery specification of ± 10 % or 600 mg/dL (6.78 mmol/L) with a recovery specification of ± 15 %.

Total protein: No significant interference from 4‑11 g/dL total protein.

Albumin: No significant interference from albumin up to a concentration of 5.4 g/dL.

Gamma globulin: No significant interference from gamma globulin up to a concentration of 6.2 g/dL.

Cholesterol: No significant interference from cholesterol up to a concentration of 350 mg/dL.

Creatinine: No significant interference from creatinine up to a concentration of 10 mg/dL.

Uric acid: No significant interference from uric acid up to a concentration of 20 mg/dL.

There is the possibility that other substances and/or factors may interfere with the test and cause unreliable results.

In very rare cases, gammopathy, in particular type IgM (Waldenström’s macroglobulinemia), may cause unreliable results.

LREFBakker AJ, Mücke M. Gammopathy interference in clinical chemistry assays: mechanisms, detection and prevention. Clin Chem Lab Med 2007;45(9):1240-1243.

For diagnostic purposes, the results should always be assessed in conjunction with the patient’s medical history, clinical examination and other findings.

ACTION REQUIRED
Special Wash Programming: The use of special wash steps is mandatory when certain test combinations are run together on cobas c systems. The latest version of the carry‑over evasion list can be found with the NaOHD-SMS-SmpCln1+2-SCCS Method Sheets. For further instructions refer to the operator’s manual. cobas c 502 analyzer: All special wash programming necessary for avoiding carry‑over is available via the cobas link, manual input is required in certain cases.

Where required, special wash/carry‑over evasion programming must be implemented prior to reporting results with this test.

", "Language": "en" }, { "Name": "OrderInformation", "Value": "

OrderInformation (CC Reagents - cobas + Integra)

Order information

Analyzer(s) on which cobas c pack(s) can be used

04357213190

Mycophenolic Acid (100 tests)

System‑ID 07 6823 5

cobas c 311, cobas c 501/502

Materials required (but not provided):

04357221190

Total MPA Calibrators
A‑F (1 x 5 mL)
Diluent (1 x 10 mL)

System‑ID 07 6824 3
Codes 490‑495

04357230190

Total MPA Controls
Level I (2 x 5 mL)
Level II (2 x 5 mL)
Level III (2 x 5 mL)


Code 107
Code 108
Code 109

", "Language": "en" }, { "Name": "SystemInformation", "Value": "

System information

For cobas c 311/501 analyzers:

TMPA: ACN 623

For cobas c 502 analyzer:

TMPA: ACN 8623

", "Language": "en" }, { "Name": "Handling", "Value": "

Reagent handling

Ready for use

", "Language": "en" }, { "Name": "TestDefinition", "Value": "

Application for serum and plasma

Deselect Automatic Rerun for these applications in the Utility menu, Application screen, Range tab.

cobas c 311 test definition

Assay type

Rate‑A

Reaction time / Assay points

10 / 40‑57

Wavelength (sub/main)

415/340 nm

Reaction direction

Increase

Unit

µg/mL

Reagent pipetting

Diluent (H2O)

R1

180 µL

R2

19 µL

Sample volumes

Sample

Sample dilution

Sample

Diluent (NaCl)

Normal

3.0 µL

Decreased

3.0 µL

Increased

3.0 µL

cobas c 501/502 test definition

Assay type

Rate‑A

Reaction time / Assay points

10 / 54‑70

Wavelength (sub/main)

415/340 nm

Reaction direction

Increase

Unit

µg/mL

Reagent pipetting

Diluent (H2O)

R1

180 µL

R2

19 µL

Sample volumes

Sample

Sample dilution

Sample

Diluent (NaCl)

Normal

3.0 µL

Decreased

3.0 µL

Increased

3.0 µL

", "Language": "en" }, { "Name": "StorageStability", "Value": "

Storage and stability

Shelf life at 2‑8 °C:

See expiration date on cobas c pack label

On‑board in use and refrigerated on the analyzer:

Do not freeze.

12 weeks

", "Language": "en" }, { "Name": "Calibration", "Value": "

Calibration

Calibrators

S1‑6: Total MPA Calibrators

Calibration mode

RCM

Calibration frequency

6‑point calibration

- after reagent lot change and every 2 weeks

- as required following quality control procedures

Calibration interval may be extended based on acceptable verification of calibration by the laboratory.

Traceability: The Total MPA Calibrators are prepared to contain known quantities of mycophenolic acid in normal human serum and are traceable to a primary reference method (HPLC).

LREFBrandhorst G, Streit F, Goetze S, et al. Quantification by liquid chromatography tandem mass spectrometry of mycophenolic acid and its phenol and acyl glucuronide metabolites. Clin Chem 2006;52:1962-1964.

", "Language": "en" }, { "Name": "Limitations", "Value": "", "Language": "en" }, { "Name": "PerformanceData", "Value": "

Specific performance data

Representative performance data on the analyzers are given below. Results obtained in individual laboratories may differ.

", "Language": "en" }, { "Name": "Precision", "Value": "

Precision

Precision was determined using human samples and controls in accordance with the CLSI (Clinical and Laboratory Standards Institute) EP5 requirements with repeatability (n = 63) and intermediate precision (3 aliquots per run, 1 run per day, 21 days). The following results were obtained on a cobas c 501 analyzer.

Serum/Plasma

Repeatability

Mean

SD

CV

µg/mL (µmol/L)

µg/mL (µmol/L)

%

Control 1

0.85 (2.65)

0.02 (0.06)

2.4

Control 2

3.46 (10.8)

0.03 (0.1)

0.8

Control 3

12.2 (38.1)

0.1 (0.3)

0.7

HP 1a

1.51 (4.71)

0.03 (0.09)

1.9

HP 2a

6.22 (19.4)

0.08 (0.3)

1.3

Intermediate precision

Mean

SD

CV

µg/mL (µmol/L)

µg/mL (µmol/L)

%

Control 1

0.85 (2.65)

0.03 (0.09)

3.6

Control 2

3.46 (10.8)

0.06 (0.2)

1.6

Control 3

12.2 (38.1)

0.1 (0.4)

1.0

HP 1a

1.51 (4.71)

0.04 (0.12)

2.4

HP 2a

6.22 (19.4)

0.11 (0.3)

1.8

aHP 1 and HP 2 are non‑spiked clinical samples

The data obtained on cobas c 501 analyzer(s) are representative for cobas c 311 analyzer(s).

", "Language": "en" }, { "Name": "MethodComparison", "Value": "

Method comparison

Serum/plasma

Mycophenolic acid values for human plasma samples from renal and cardiac transplant patients were obtained using the cobas c 501 analyzer compared to those determined with a validated MPA HPLC method. These same samples were also compared to values obtained on the COBAS INTEGRA 400/800 analyzers. The sample population for this internal study included 88 renal and 70 cardiac samples from post‑transplant patients. Other demographics for this sample population are unknown. Passing‑Bablok statistics for the correlation are included in the method comparison table below.

LREFBablok W, Passing H, Bender R, et al. A general regression procedure for method transformation. Application of linear regression procedures for method comparison studies in clinical chemistry, Part III. J Clin Chem Clin Biochem 1988 Nov;26(11):783-790.

Methodology

Slope
(95 % CI)

Intercept
(95 %  CI)

Correlation
Coefficient

Sample
Size

Sample
Range
(µg/mL)

cobas c 501 analyzer vs. HPLC

Renal

1.043 (1.025-
1.060)

0.054 (0.010-
0.093)

0.997

88

0.460-13.6

Cardiac

1.109 (1.077-
1.141)

-0.077 (-0.147-
0.005)

0.991

70

0.573-14.2

Combined

1.062 (1.043-
1.084)

0.016 (-0.029-
0.057)

0.994

158

0.460-14.2

cobas c 501 analyzer vs. COBAS INTEGRA 400 analyzer

Combined

0.996 (0.990-
1.00)

-0.032 (-0.040-
(-0.014))

1.000

161

0.44-14.0

cobas c 501 analyzer vs. COBAS INTEGRA 800 analyzer

Combined

0.977 (0.971-
0.984)

0.000 (-0.018-
0.014)

0.999

160

0.48-15.0

The following graph shows the correlation testing of the Roche Total MPA assay on the cobas c 501 analyzer vs HPLC with the combined renal and cardiac samples from the above table.

The same data set from the regression plot above is depicted in the Bland‑Altman difference plot shown below.

N = 158

Mean (Y-X) = 0.36

SD (Y-X) = 0.54

1.96 SD = 1.07

Mean + 1.96 SD = 1.43

Mean – 1.96 SD = - 0.70

In a separate study, mycophenolic acid values for human plasma samples obtained with the Roche Total Mycophenolic Acid assay on COBAS INTEGRA analyzers were compared to those using independent validated MPA HPLC methods. Samples from renal and cardiac transplant patients were tested at two external clinical sites with concurrent HPLC testing at each site.

The external trial included a total of 412 samples collected from post-transplant patients. The sample population for the COBAS INTEGRA 400 plus analyzer study included 265 samples (148 renal and 117 cardiac) from a total of 209 “routine” adult transplant recipients. Samples tested on the COBAS INTEGRA 800 analyzer were obtained from an international trial of renal transplant recipients (147 samples from 86 adult patients). The Passing-Bablok statistics of the correlations are shown in the table below.

Methodology

Slope
(95 % CI)

Intercept
(95 % CI)

Correlation
Coefficient

Sample
Size

Sample Range
(µg/mL)

COBAS
INTEGRA 400 plus analyzer vs. HPLC

1.011 (1.000-
1.025)

0.064 (0.038-
0.090)

0.993

265

0.4-14.8

COBAS
INTEGRA  800 analyzer vs. HPLC

1.100 (1.073-
1.120)

-0.120
(-0.192-
(-0.066))

0.994

147

0.5-14.7

The data obtained on cobas c 501 analyzer(s) are representative for cobas c 311 analyzer(s).

", "Language": "en" }, { "Name": "Summary", "Value": "

Summary

Mycophenolic acid is prescribed as mycophenolate mofetil (MMF), a morpholino ester, or as mycophenolate sodium. The MMF prodrug is rapidly metabolized to the active compound, MPA, via cleavage of the ester linkage.

LREFWeber LT, Shipkova M, Armstrong VW, et al. The pharmacokinetic-pharmacodynamic relationship for total and free mycophenolic acid in pediatric renal transplant recipients: A report of the German study group on mycophenolate mofetil therapy. J Am Soc Nephrol 2002;13:759-768.
MPA inhibits de novo purine biosynthesis by the reversible, noncompetitive inhibition of inosine monophosphate dehydrogenase (IMPDH‑II).
LREFWeber LT, Shipkova M, Armstrong VW, et al. The pharmacokinetic-pharmacodynamic relationship for total and free mycophenolic acid in pediatric renal transplant recipients: A report of the German study group on mycophenolate mofetil therapy. J Am Soc Nephrol 2002;13:759-768.
,
LREFShaw LM, Nichols A, Hale M, et al. Therapeutic monitoring of mycophenolic acid: A consensus panel report. Clin Biochem 1998;31(5):317-322.
The inhibition of IMPDH‑II in activated lymphocytes reduces intracellular guanine nucleotide pools, thus arresting lymphocyte proliferation.
LREFWu JC. Mycophenolate mofetil: molecular mechanism of action. Perspect Drug Discovery Design 1994;2:185-204.
,
LREFRansom JT. The mechanism of action of mycophenolate mofetil. Ther Drug Monit 1995;17:681-684.

MPA is metabolized in the liver by glucuronidation at the phenolic hydroxyl group to the pharmacologically inactive mycophenolic acid glucuronide (MPAG). Plasma levels of MPAG are approximately 40‑fold higher than those of the parent drug.

LREFSchutz E, Shikova M, Armstrong VW, et al. Therapeutic drug monitoring of mycophenolic acid: comparison of HPLC and immunoassay reveals new metabolites. Transplant Proc 1998;30:1185-1187.
,
LREFIndjova D, Kassabova L, Svinarov D. Simultaneous determination of mycophenolic acid and its phenolic glucuronide in human plasma using an isocratic high-performance liquid chromatography procedure. J Chromatogr B Analyt Technol Biomed Life Sci 2005 Mar 25;817(2):327-330.
In addition to the primary metabolite, two additional metabolites of MPA have been identified, the acyl glucuronide (Ac‑MPAG) and the phenolic glucoside of MPA. Of these two, only the acyl glucuronide is able to inhibit IMPDH‑II in vitro.
LREFWeber LT, Shipkova M, Armstrong VW, et al. The pharmacokinetic-pharmacodynamic relationship for total and free mycophenolic acid in pediatric renal transplant recipients: A report of the German study group on mycophenolate mofetil therapy. J Am Soc Nephrol 2002;13:759-768.

Growing clinical evidence indicates that therapeutic drug monitoring of MPA can maximize the therapeutic benefit of the drug and minimize its adverse effects.

LREFMeiser BM. Therapeutic drug monitoring of mycophenolic acid in cardiac tranplant recipients: does it make sense? Curr Opin Organ Transplant 2005;10:350-354.
,
LREFGajarski RJ, Crowley DC, Zamberlan MC, et al. Lack of correlation between MMF dose and MPA level in pediatric and young adult cardiac transplant patients: Does the MPA level matter? Am J Transplant 2004;4:1495-1500.
,
LREFDipchand AI, Pietra B, McCrindle BW, et al. Mycophenolic acid levels in pediatric heart transplant recipients receiving mycophenolate mofetil. J Heart Lung Transplant 2001;20(10):1035-1043.
,
LREFKuypers DRJ. Immunosuppressive drug monitoring- What to use in clinical practice today to improve renal graft outcome? Transplant International 2005;18:140-150.
,
LREFHessilink DA, van Gelder T. The influence of cyclosporine on mycophenolic acid plasma concentrations: A review. Transplant Rev 2003;17(3):158-163.
It is generally co‑administered with calcineurin inhibitors (cyclosporine or tacrolimus) and, more recently, other immunosuppressants including sirolimus.
LREFMeiser BM. Therapeutic drug monitoring of mycophenolic acid in cardiac tranplant recipients: does it make sense? Curr Opin Organ Transplant 2005;10:350-354.
,
LREFVan Gelder T, Meur YL, Shaw LM, et al. Therapeutic drug monitoring of mycophenolate mofetil in transplantation. Ther Drug Monit 2006;28(2):145-154.

Peak levels of MPA in plasma occur approximately 1 to 2 hours after oral dosing. A secondary peak then occurs 6 to 12 hours after dosing due to enterohepatic recirculation of the drug. The pharmacokinetics of MPA exhibit wide between‑patient variability and may be altered in specific patient populations due to concomitant disease states or interactions with other immunosuppressants.

LREFCox VC, Ensom MHH. Mycophenolate mofetil for solid organ transplantation: Does the evidence support the need for clinical pharmacokinetic monitoring? Ther Drug Monit 2003;25(2):137-157.
,
LREFShaw LM, Korecka M, Venkataramanan R, et al. Mycophenolic acid pharmacodynamics and pharmacokinetics provide a basis for rational monitoring strategies. Am J Transplant 2003;3:534-542.
,
LREFShaw LM, Holt DW, Oellerich M, et al. Current issues in therapeutic drug monitoring of mycophenolic acid: Report of a roundtable discussion. Ther Drug Monit 2001;23(4):305-315.
Cyclosporine inhibits the transport of MPAG from hepatocytes into bile, resulting in decreased enterohepatic recirculation.
LREFShaw LM, Holt DW, Oellerich M, et al. Current issues in therapeutic drug monitoring of mycophenolic acid: Report of a roundtable discussion. Ther Drug Monit 2001;23(4):305-315.
Thus, in comparison to tacrolimus coadministration, MPA plasma levels may be reduced with coadministration of cyclosporine. Due to the variability in patient plasma MPA levels, monitoring MPA levels may help to optimize outcomes in patients with high risks of organ rejection after transplantation.
LREFVan Gelder T, Meur YL, Shaw LM, et al. Therapeutic drug monitoring of mycophenolate mofetil in transplantation. Ther Drug Monit 2006;28(2):145-154.
,
LREFMeiser BM, Pfeiffer M, Schmidt D, et al. Combination therapy with tacrolimus and mycophenolate mofetil following cardiac transplantation:importance of mycophenolic acid therapeutic drug monitoring. J Heart Lung Transplant 1999;18(2):143-149.

", "Language": "en" }, { "Name": "Reagents", "Value": "

Reagents - working solutions

R1

IMPDH‑II in buffer: 15.7 U/L; IMP: 4.8 mmol/L; stabilizer; preservative

R2

NAD: 10 mmol/L in buffer; stabilizer; preservative.

R1 is in position A and R2 is in position B.

", "Language": "en" }, { "Name": "PrecautionsWarnings", "Value": "

Precautions and warnings

For in vitro diagnostic use for health care professionals. Exercise the normal precautions required for handling all laboratory reagents.

Infectious or microbial waste:
Warning: handle waste as potentially biohazardous material. Dispose of waste according to accepted laboratory instructions and procedures.

Environmental hazards:
Apply all relevant local disposal regulations to determine the safe disposal.

Safety data sheet available for professional user on request.

For USA: Caution: Federal law restricts this device to sale by or on the order of a physician.

This kit contains components classified as follows in accordance with the Regulation (EC) No. 1272/2008:

Danger

H350

May cause cancer.

Prevention:

P201

Obtain special instructions before use.

P202

Do not handle until all safety precautions have been read and understood.

P280

Wear protective gloves/ protective clothing/ eye protection/ face protection/ hearing protection.

Response:

P308 + P313

IF exposed or concerned: Get medical advice/attention.

Storage:

P405

Store locked up.

Disposal:

P501

Dispose of contents/container to an approved waste disposal plant.

EUH 208

Contains Sodium Hydroxymethylglycinate. May produce an allergic reaction.

Product safety labeling follows EU GHS guidance.

Contact phone: all countries: +49-621-7590, USA: 1-800-428-2336

", "Language": "en" }, { "Name": "Caution", "Value": "", "Language": "en" }, { "Name": "QualityControl", "Value": "

Quality control

For quality control, use control materials as listed in the \"Order information\" section.

In addition, other suitable control material can be used.

The control intervals and limits should be adapted to each laboratory’s individual requirements. Values obtained should fall within the defined limits. Each laboratory should establish corrective measures to be taken if values fall outside the defined limits.

Follow the applicable government regulations and local guidelines for quality control.

", "Language": "en" }, { "Name": "SpecimenPreparation", "Value": "

Specimen collection and preparation

For specimen collection and preparation only use suitable tubes or collection containers.

Only the specimens listed below were tested and found acceptable.
Serum: Collect serum using standard sampling tubes.
Plasma: K2‑ and K3‑EDTA plasma.

The sample types listed were tested with a selection of sample collection tubes that were commercially available at the time of testing, i.e. not all available tubes of all manufacturers were tested. Sample collection systems from various manufacturers may contain differing materials which could affect the test results in some cases. When processing samples in primary tubes (sample collection systems), follow the instructions of the tube manufacturer.

Centrifuge samples containing precipitates before performing the assay.

See the limitations and interferences section for details about possible sample interferences.

Sample stability claims were established by experimental data by the manufacturer or based on reference literature and only for the temperatures/time frames as stated in the method sheet. It is the responsibility of the individual laboratory to use all available references and/or its own studies to determine specific stability criteria for its laboratory.

Specimens should be tested within 8 hours of collection if kept at room temperature. If specimens must be stored for later testing, they should be kept at 2 to 8 °C for up to 96 hours or at -20 °C or below for up to 11 months.

LREFShaw LM, Holt DW, Oellerich M, et al. Current issues in therapeutic drug monitoring of mycophenolic acid: Report of a roundtable discussion. Ther Drug Monit 2001;23(4):305-315.
,
LREFShipkova M, Armstrong VM, Schneider T, et al. Stability of mycophenolic acid glucuronide in human plasma. Clin Chem 1999;45(1):127-129.
Specimens should not be repeatedly frozen and thawed (do not exceed 5 freeze/thaw cycles).

Invert thawed specimens several times prior to testing.

", "Language": "en" } ] } }, { "ProductSpecVariant": { "MetaData": { "DocumentMaterialNumber": "0208105634190c503", "ProductName": "MPA", "ProductLongName": "Mycophenolic Acid", "Language": "en", "DocumentVersion": "2", "DocumentObjectID": "FF00000004A4330E", "DocumentOriginID": "FF00000003D9FE0E", "MaterialNumbers": [ "08105634190" ], "InstrumentReferences": [ { "ID": "9493", "BrandName": "cobas c 303" }, { "ID": "8481", "BrandName": "cobas c 503" } ], "DisclaimerText": "Product information shown on this page contains elements of the officially released Method Sheet. If you require further information please refer to the full Method Sheet PDF under the given link, or contact your local Roche country representative." }, "Chapters": [ { "Name": "IntendedUse", "Value": "

Intended use

In vitro test for the quantitative determination of total mycophenolic acid in serum or plasma as an aid in the management of mycophenolic acid therapy in renal and cardiac transplant patients on Roche/Hitachi cobas c systems.

", "Language": "en" }, { "Name": "TestPrinciple", "Value": "

Test principle

The Roche Total MPA assay is a two‑reagent system containing IMP (inosine monophosphate), NAD (nicotinamide adenine dinucleotide), and a mutant IMPDH II (inosine monophosphate dehydrogenase) enzyme. The reagents used to measure MPA concentrations in serum or plasma mimic the in vivo mechanism of the enzyme. In vivo, IMPDH II combines with IMP and NAD to form a complex. The NAD is reduced to form NADH, and IMP is converted to XMP. The NADH leaves the enzyme first. When MPA is present, the XMP is not released from the enzyme.

In the Roche Total MPA assay, a fixed amount of mutant IMPDH in the reagent combines with fixed amounts of IMP and NAD in the reagents. The formation of NADH is measured at 340 nm. When MPA is present in the serum or plasma sample, the formation of NADH by the reagents is inhibited, as measured by a decrease in the signal at 340 nm. MPA concentration is inversely proportional to the rate of NADH formation. The reaction has been optimized for a non‑linear, six‑point calibration.

", "Language": "en" }, { "Name": "MeasuringRange", "Value": "

Limits and ranges

Measuring range

0.4‑15 µg/mL (1.2‑46.8 µmol/L)

Manually dilute samples above the measuring range with the diluent (equivalent to the 0 µg/mL calibrator) from the Roche Total MPA Calibrators (1 part sample + 4 parts diluent) and reassay. Multiply the result by 5 to obtain the specimen value.

Lower limits of measurement

Limit of Blank, Limit of Detection and Limit of Quantitation

Limit of Blank

= 0.4 µg/mL (1.2 µmol/L)

Limit of Detection

= 0.4 µg/mL (1.2 µmol/L)

Limit of Quantitation

= 0.4 µg/mL (1.2 µmol/L)

The Limit of Blank, Limit of Detection and Limit of Quantitation were determined in accordance with the CLSI (Clinical and Laboratory Standards Institute) EP17‑A2 requirements.

The Limit of Blank is the 95th percentile value from n ≥ 60 measurements of analyte‑free samples over several independent series. The Limit of Blank corresponds to the concentration below which analyte‑free samples are found with a probability of 95 %.

The Limit of Detection is determined based on the Limit of Blank and the standard deviation of low concentration samples.

The Limit of Detection corresponds to the lowest analyte concentration which can be detected (value above the Limit of Blank with a probability of 95 %).

The Limit of Quantitation is the lowest analyte concentration that can be reproducibly measured with a total error of 20 %. It has been determined using low concentration mycophenolic acid samples.

", "Language": "en" }, { "Name": "ExpectedValues", "Value": "

Expected values

The therapeutic range of mycophenolic acid is not yet fully established and is dependent on transplant type and coadministered drugs. Optimal mycophenolic acid assay values to prevent rejection may vary based on the test system and therefore should be established for each test system. Laboratories should include identification of the assay or method used in order to aid in interpretation of the results.

Optimal ranges depend on the patient’s clinical state, coadministration of other immunosuppressants, time post‑transplant and a number of other factors. Therefore, individual MPA values cannot be used as the sole indicator for making changes in treatment regimen and each patient should be thoroughly evaluated clinically before changes in treatment regimens are made.

Decreased incidences of rejection in the early months post‑transplantation have been reported in renal transplant patients with predose MPA concentrations (measured by HPLC) of ≥ 1.3 µg/mL (≥ 4.06 µmol/L) with coadministration of cyclosporine and ≥ 1.9 µg/mL (≥ 5.93 µmol/L) with coadministration of tacrolimus.

LREFVan Gelder T, Meur YL, Shaw LM, et al. Therapeutic drug monitoring of mycophenolate mofetil in transplantation. Ther Drug Monit 2006;28(2):145-154.
,
LREFCox VC, Ensom MHH. Mycophenolate mofetil for solid organ transplantation: Does the evidence support the need for clinical pharmacokinetic monitoring? Ther Drug Monit 2003;25(2):137-157.
An upper therapeutic range based on development of toxicity has not been established. The clinical ramifications of MPA concentrations beyond the early post transplantation periods are not yet known.
LREFVan Gelder T, Meur YL, Shaw LM, et al. Therapeutic drug monitoring of mycophenolate mofetil in transplantation. Ther Drug Monit 2006;28(2):145-154.

In cardiac transplant patients, predose MPA concentrations (measured by HPLC) of 1.2‑3.5 µg/mL (3.75‑10.9 µmol/L) have been recommended to minimize incidences of rejection.

LREFMeiser BM. Therapeutic drug monitoring of mycophenolic acid in cardiac tranplant recipients: does it make sense? Curr Opin Organ Transplant 2005;10:350-354.
,
LREFVan Gelder T, Meur YL, Shaw LM, et al. Therapeutic drug monitoring of mycophenolate mofetil in transplantation. Ther Drug Monit 2006;28(2):145-154.
Higher pre‑dose concentrations (≥ 2.5 µg/mL, ≥ 7.81 µmol/L) in the early post‑transplantation period (< 6 months) have also been suggested.
LREFMeiser BM. Therapeutic drug monitoring of mycophenolic acid in cardiac tranplant recipients: does it make sense? Curr Opin Organ Transplant 2005;10:350-354.
,
LREFGajarski RJ, Crowley DC, Zamberlan MC, et al. Lack of correlation between MMF dose and MPA level in pediatric and young adult cardiac transplant patients: Does the MPA level matter? Am J Transplant 2004;4:1495-1500.
,
LREFMeiser BM, Reichart B. New agents and new strategies in immunosuppression after heart transplantation. Curr Opin Organ Transplant 2002;7:226-232.
Pediatric cardiac transplant patients have been shown to require higher doses of MPA in comparison to adults due to differences in MPA metabolism.
LREFMeiser BM. Therapeutic drug monitoring of mycophenolic acid in cardiac tranplant recipients: does it make sense? Curr Opin Organ Transplant 2005;10:350-354.
,
LREFGajarski RJ, Crowley DC, Zamberlan MC, et al. Lack of correlation between MMF dose and MPA level in pediatric and young adult cardiac transplant patients: Does the MPA level matter? Am J Transplant 2004;4:1495-1500.
,
LREFDipchand AI, Pietra B, McCrindle BW, et al. Mycophenolic acid levels in pediatric heart transplant recipients receiving mycophenolate mofetil. J Heart Lung Transplant 2001;20(10):1035-1043.

Each laboratory should investigate the transferability of the expected values to its own patient population and if necessary determine its own reference ranges.

", "Language": "en" }, { "Name": "LimitationInterference", "Value": "

Limitations - interference

See the Analytical specificity section of this insert for information on substances tested for cross‑reactivity in this assay. There is the possibility that other substances and/or factors may interfere with the test and cause erroneous results (e.g., technical or procedural errors). Specimens with assay values greater than the highest calibrator will be flagged by the system and must be repeated after appropriate dilution of the original sample with the zero calibrator or with the diluent from the Total MPA Calibrator kit.

Criterion: Recovery within ± 10 % of initial value at MPA concentrations of approximately 1‑5 µg/mL (3.1‑15.6 µmol/L) and 8‑12 µg/mL (25.0‑37.5 µmol/L).

Serum/Plasma

Icterus:

LREFGlick MR, Ryder KW, Jackson SA. Graphical Comparisons of Interferences in Clinical Chemistry Instrumentation. Clin Chem 1986;32:470-475.
No significant interference up to an I index of 66 for conjugated bilirubin and 17 for unconjugated bilirubin (approximate conjugated bilirubin concentration: 1129 µmol/L or 66 mg/dL; approximate unconjugated bilirubin concentration: 291 µmol/L or 17 mg/dL).

Hemolysis:

LREFGlick MR, Ryder KW, Jackson SA. Graphical Comparisons of Interferences in Clinical Chemistry Instrumentation. Clin Chem 1986;32:470-475.
No significant interference up to an H index of 1000 (approximate hemoglobin concentration: 621 µmol/L or 1000 mg/dL).

Lipemia (Intralipid):

LREFGlick MR, Ryder KW, Jackson SA. Graphical Comparisons of Interferences in Clinical Chemistry Instrumentation. Clin Chem 1986;32:470-475.
No significant interference up to an L index of 93. There is poor correlation between the L index (corresponds to turbidity) and triglycerides concentration.

Avoid the use of lipemic specimens.

Triglycerides: No significant interference from triglycerides up to a concentration of 500 mg/dL (5.65 mmol/L) with a recovery specification of ± 10 % or 600 mg/dL (6.78 mmol/L) with a recovery specification of ± 15 %.

Total protein: No significant interference from 4‑11 g/dL total protein.

Albumin: No significant interference from albumin up to a concentration of 5.4 g/dL.

Gamma globulin: No significant interference from gamma globulin up to a concentration of 6.2 g/dL.

Cholesterol: No significant interference from cholesterol up to a concentration of 350 mg/dL.

Creatinine: No significant interference from creatinine up to a concentration of 10 mg/dL.

Uric acid: No significant interference from uric acid up to a concentration of 20 mg/dL.

There is the possibility that other substances and/or factors may interfere with the test and cause unreliable results.

In very rare cases, gammopathy, in particular type IgM (Waldenström’s macroglobulinemia), may cause unreliable results.

LREFBakker AJ, Mücke M. Gammopathy interference in clinical chemistry assays: mechanisms, detection and prevention. Clin Chem Lab Med 2007;45(9):1240-1243.

For diagnostic purposes, the results should always be assessed in conjunction with the patient’s medical history, clinical examination and other findings.

ACTION REQUIRED
Special Wash Programming: The use of special wash steps is mandatory when certain test combinations are run together on cobas c systems. All special wash programming necessary for avoiding carry-over is available via the cobas link. The latest version of the carry-over evasion list can be found with the NaOHD/SMS/SCCS Method Sheet. For further instructions, refer to the operator’s manual.

", "Language": "en" }, { "Name": "OrderInformation", "Value": "

OrderInformation (CC Reagents - cobas + Integra)

Order information

Analyzer(s) on which cobas c pack(s) can be used

08105634190

Mycophenolic Acid (100 tests)

System‑ID 2090 001

cobas c 303, cobas c 503

04357221190

Total MPA Calibrators
A‑F (1 x 5 mL)
Diluent (1 x 10 mL)

System‑ID 07 6824 3
Codes 20490‑20495

04357230190

Total MPA Controls
Level I (2 x 5 mL)
Level II (2 x 5 mL)
Level III (2 x 5 mL)


Code 20107
Code 20108
Code 20109

", "Language": "en" }, { "Name": "SystemInformation", "Value": "

System information

MPA: ACN 20900

", "Language": "en" }, { "Name": "Handling", "Value": "

Reagent handling

Ready for use

", "Language": "en" }, { "Name": "TestDefinition", "Value": "

Application for serum and plasma

Test definition

Reporting time

10 min

Wavelength (sub/main)

415/340 nm

Reagent pipetting

Diluent (H2O)

R1

132 µL

R2

14 µL

15 µL

Sample volumes

Sample

Sample dilution

Sample

Diluent (NaCl)

Normal

2.2 µL

Decreased

2.2 µL

Increased

2.2 µL

For further information about the assay test definitions refer to the application parameters setting screen of the corresponding analyzer and assay.

", "Language": "en" }, { "Name": "StorageStability", "Value": "

Storage and stability

Shelf life at 2‑8 °C:

See expiration date on cobas c pack label

On‑board in use and refrigerated on the analyzer:

Do not freeze.

12 weeks

", "Language": "en" }, { "Name": "Calibration", "Value": "

Calibration

Calibrators

S1‑6: Total MPA Calibrators

Calibration mode

Non‑linear

Calibration frequency

Full calibration
- after reagent lot change and every 2 weeks
- as required following quality control procedures

Calibration interval may be extended based on acceptable verification of calibration by the laboratory.

Traceability: The Total MPA Calibrators are prepared to contain known quantities of mycophenolic acid in normal human serum and are traceable to a primary reference method (HPLC).

LREFBrandhorst G, Streit F, Goetze S, et al. Quantification by liquid chromatography tandem mass spectrometry of mycophenolic acid and its phenol and acyl glucuronide metabolites. Clin Chem 2006;52:1962-1964.

", "Language": "en" }, { "Name": "Limitations", "Value": "", "Language": "en" }, { "Name": "PerformanceData", "Value": "

Specific performance data

Representative performance data on the analyzers are given below. These data represent the performance of the analytical procedure itself.

Results obtained in individual laboratories may differ due to heterogenous sample materials, aging of analyzer components and mixture of reagents running on the analyzer.

", "Language": "en" }, { "Name": "Precision", "Value": "

Precision

Precision was determined using human samples and controls in accordance with the CLSI (Clinical and Laboratory Standards Institute) EP05‑A3 requirements with repeatability (n = 84) and intermediate precision (2 aliquots per run, 2 runs per day, 21 days). Results for repeatability and intermediate precision were obtained on the cobas c 503 analyzer.

Serum/Plasma

Repeatability

Mean

SD

CV

µg/mL (µmol/L)

µg/mL (µmol/L)

%

TMPA 1a)

0.893 (2.79)

0.0120 (0.0375)

1.3

TMPA 2b)

3.47 (10.8)

0.0189 (0.0590)

0.5

TMPA 3c)

11.8 (36.8)

0.0951 (0.297)

0.8

Human serum 1

0.851 (2.66)

0.0144 (0.0450)

1.7

Human serum 2

1.47 (4.59)

0.0146 (0.0456)

1.0

Human serum 3

2.11 (6.59)

0.0150 (0.0468)

0.7

Human serum 4

8.27 (25.8)

0.0600 (0.187)

0.7

Human serum 5

14.1 (44.0)

0.149 (0.465)

1.1

Intermediate precision

Mean

SD

CV

µg/mL (µmol/L)

µg/mL (µmol/L)

%

TMPA 1

FREFTotal MPA Control Level I

0.901 (2.81)

0.0190 (0.0593)

2.1

TMPA 2

FREFTotal MPA Control Level II

3.46 (10.8)

0.0303 (0.0946)

0.9

TMPA 3

FREFTotal MPA Control Level III

11.8 (36.8)

0.106 (0.331)

0.9

Human serum 1

0.851 (2.66)

0.0216 (0.0674)

2.5

Human serum 2

1.47 (4.59)

0.0227 (0.0709)

1.5

Human serum 3

2.12 (6.62)

0.0264 (0.0824)

1.2

Human serum 4

8.33 (26.0)

0.0748 (0.234)

0.9

Human serum 5

14.1 (44.0)

0.197 (0.615)

1.4

", "Language": "en" }, { "Name": "MethodComparison", "Value": "

Method comparison

Mycophenolic acid values for human serum and plasma samples obtained on a cobas c 503 analyzer (y) were compared with those determined using the corresponding reagent on a cobas c 501 analyzer (x).

Serum/plasma

Sample size (n) = 74

Passing/Bablok

LREFBablok W, Passing H, Bender R, et al. A general regression procedure for method transformation. Application of linear regression procedures for method comparison studies in clinical chemistry, Part III. J Clin Chem Clin Biochem 1988 Nov;26(11):783-790.

Linear regression

y = 0.995x + 0.00222 µg/mL

y = 0.998x - 0.0186 µg/mL

τ = 0.994

r = 1.000

The sample concentrations were between 0.620 and 14.5 µg/mL (1.94 and 45.3 µmol/L).

Mycophenolic acid values for human serum and plasma samples obtained on a cobas c 303 analyzer (y) were compared with those determined using the corresponding reagent on a cobas c 501 analyzer (x).

Serum/plasma

Sample size (n) = 74

Passing/Bablok

LREFBablok W, Passing H, Bender R, et al. A general regression procedure for method transformation. Application of linear regression procedures for method comparison studies in clinical chemistry, Part III. J Clin Chem Clin Biochem 1988 Nov;26(11):783-790.

Linear regression

y = 0.975x - 0.0146 µg/mL

y = 0.974x - 0.0165 µg/mL

τ = 0.991

r = 1.000

The sample concentrations were between 0.580 and 14.9 µg/mL (1.81 and 46.5 µmol/L).

Mycophenolic acid values for human plasma samples from renal and cardiac transplant patients were obtained using the cobas c 501 analyzer compared to those determined with a validated MPA HPLC method. These same samples were also compared to values obtained on the COBAS INTEGRA 400/800 analyzers. The sample population for this internal study included 88 renal and 70 cardiac samples from post‑transplant patients. Other demographics for this sample population are unknown. Passing‑Bablok statistics for the correlation are included in the method comparison table below.

LREFBablok W, Passing H, Bender R, et al. A general regression procedure for method transformation. Application of linear regression procedures for method comparison studies in clinical chemistry, Part III. J Clin Chem Clin Biochem 1988 Nov;26(11):783-790.

Methodology

Slope
(95 % CI)

Intercept
(95 %  CI)

Correlation
Coefficient

Sample
Size

Sample
Range
(µg/mL)

cobas c 501 analyzer vs. HPLC

Renal

1.043 (1.025-
1.060)

0.054 (0.010-
0.093)

0.997

88

0.460-13.6

Cardiac

1.109 (1.077-
1.141)

-0.077 (-0.147-
0.005)

0.991

70

0.573-14.2

Combined

1.062 (1.043-
1.084)

0.016 (-0.029-
0.057)

0.994

158

0.460-14.2

cobas c 501 analyzer vs. COBAS INTEGRA 400 analyzer

Combined

0.996 (0.990-
1.00)

-0.032 (-0.040-
(-0.014)

1.000

161

0.44-14.0

cobas c 501 analyzer vs. COBAS INTEGRA 800 analyzer

Combined

0.977 (0.971-
0.984)

0.000 (-0.018-
0.014)

0.999

160

0.48-15.0

The following graph shows the correlation testing of the Roche Total MPA assay on the cobas c 501 analyzer vs HPLC with the combined renal and cardiac samples from the above table.

The same data set from the regression plot above is depicted in the Bland‑Altman difference plot shown below.

N = 158

Mean (Y-X) = 0.36

SD (Y-X) = 0.54

1.96 SD = 1.07

Mean + 1.96 SD = 1.43

Mean – 1.96 SD = - 0.70

In a separate study, mycophenolic acid values for human plasma samples obtained with the Roche Total Mycophenolic Acid assay on COBAS INTEGRA analyzers were compared to those using independent validated MPA HPLC methods. Samples from renal and cardiac transplant patients were tested at two external clinical sites with concurrent HPLC testing at each site.

The external trial included a total of 412 samples collected from post-transplant patients. The sample population for the COBAS INTEGRA 400 plus analyzer study included 265 samples (148 renal and 117 cardiac) from a total of 209 “routine” adult transplant recipients. Samples tested on the COBAS INTEGRA 800 analyzer were obtained from an international trial of renal transplant recipients (147 samples from 86 adult patients). The Passing-Bablok statistics of the correlations are shown in the table below.

Methodology

Slope
(95 % CI)

Intercept
(95 % CI)

Correlation
Coefficient

Sample
Size

Sample Range
(µg/mL)

COBAS
INTEGRA 400 plus analyzer vs. HPLC

1.011 (1.000-
1.025)

0.064 (0.038-
0.090)

0.993

265

0.4-14.8

COBAS
INTEGRA  800 analyzer vs. HPLC

1.100 (1.073-
1.120)

-0.120
(-0.192-
(-0.066)

0.994

147

0.5-14.7

", "Language": "en" }, { "Name": "Summary", "Value": "

Summary

Mycophenolic acid is prescribed as mycophenolate mofetil (MMF), a morpholino ester, or as mycophenolate sodium. The MMF prodrug is rapidly metabolized to the active compound, MPA, via cleavage of the ester linkage.

LREFWeber LT, Shipkova M, Armstrong VW, et al. The pharmacokinetic-pharmacodynamic relationship for total and free mycophenolic acid in pediatric renal transplant recipients: A report of the German study group on mycophenolate mofetil therapy. J Am Soc Nephrol 2002;13:759-768.
MPA inhibits de novo purine biosynthesis by the reversible, noncompetitive inhibition of inosine monophosphate dehydrogenase (IMPDH‑II).
LREFWeber LT, Shipkova M, Armstrong VW, et al. The pharmacokinetic-pharmacodynamic relationship for total and free mycophenolic acid in pediatric renal transplant recipients: A report of the German study group on mycophenolate mofetil therapy. J Am Soc Nephrol 2002;13:759-768.
,
LREFShaw LM, Nichols A, Hale M, et al. Therapeutic monitoring of mycophenolic acid: A consensus panel report. Clin Biochem 1998;31(5):317-322.
The inhibition of IMPDH‑II in activated lymphocytes reduces intracellular guanine nucleotide pools, thus arresting lymphocyte proliferation.
LREFWu JC. Mycophenolate mofetil: molecular mechanism of action. Perspect Drug Discovery Design 1994;2:185-204.
,
LREFRansom JT. The mechanism of action of mycophenolate mofetil. Ther Drug Monit 1995;17:681-684.

MPA is metabolized in the liver by glucuronidation at the phenolic hydroxyl group to the pharmacologically inactive mycophenolic acid glucuronide (MPAG). Plasma levels of MPAG are approximately 40‑fold higher than those of the parent drug.

LREFSchutz E, Shikova M, Armstrong VW, et al. Therapeutic drug monitoring of mycophenolic acid: comparison of HPLC and immunoassay reveals new metabolites. Transplant Proc 1998;30:1185-1187.
,
LREFIndjova D, Kassabova L, Svinarov D. Simultaneous determination of mycophenolic acid and its phenolic glucuronide in human plasma using an isocratic high-performance liquid chromatography procedure. J Chromatogr B Analyt Technol Biomed Life Sci 2005 Mar 25;817(2):327-330.
In addition to the primary metabolite, two additional metabolites of MPA have been identified, the acyl glucuronide (Ac‑MPAG) and the phenolic glucoside of MPA. Of these two, only the acyl glucuronide is able to inhibit IMPDH‑II in vitro.
LREFWeber LT, Shipkova M, Armstrong VW, et al. The pharmacokinetic-pharmacodynamic relationship for total and free mycophenolic acid in pediatric renal transplant recipients: A report of the German study group on mycophenolate mofetil therapy. J Am Soc Nephrol 2002;13:759-768.

Growing clinical evidence indicates that therapeutic drug monitoring of MPA can maximize the therapeutic benefit of the drug and minimize its adverse effects.

LREFMeiser BM. Therapeutic drug monitoring of mycophenolic acid in cardiac tranplant recipients: does it make sense? Curr Opin Organ Transplant 2005;10:350-354.
,
LREFGajarski RJ, Crowley DC, Zamberlan MC, et al. Lack of correlation between MMF dose and MPA level in pediatric and young adult cardiac transplant patients: Does the MPA level matter? Am J Transplant 2004;4:1495-1500.
,
LREFDipchand AI, Pietra B, McCrindle BW, et al. Mycophenolic acid levels in pediatric heart transplant recipients receiving mycophenolate mofetil. J Heart Lung Transplant 2001;20(10):1035-1043.
,
LREFKuypers DRJ. Immunosuppressive drug monitoring- What to use in clinical practice today to improve renal graft outcome? Transplant International 2005;18:140-150.
,
LREFHessilink DA, van Gelder T. The influence of cyclosporine on mycophenolic acid plasma concentrations: A review. Transplant Rev 2003;17(3):158-163.
It is generally co‑administered with calcineurin inhibitors (cyclosporine or tacrolimus) and, more recently, other immunosuppressants including sirolimus.
LREFMeiser BM. Therapeutic drug monitoring of mycophenolic acid in cardiac tranplant recipients: does it make sense? Curr Opin Organ Transplant 2005;10:350-354.
,
LREFVan Gelder T, Meur YL, Shaw LM, et al. Therapeutic drug monitoring of mycophenolate mofetil in transplantation. Ther Drug Monit 2006;28(2):145-154.

Peak levels of MPA in plasma occur approximately 1 to 2 hours after oral dosing. A secondary peak then occurs 6 to 12 hours after dosing due to enterohepatic recirculation of the drug. The pharmacokinetics of MPA exhibit wide between‑patient variability and may be altered in specific patient populations due to concomitant disease states or interactions with other immunosuppressants.

LREFCox VC, Ensom MHH. Mycophenolate mofetil for solid organ transplantation: Does the evidence support the need for clinical pharmacokinetic monitoring? Ther Drug Monit 2003;25(2):137-157.
,
LREFShaw LM, Korecka M, Venkataramanan R, et al. Mycophenolic acid pharmacodynamics and pharmacokinetics provide a basis for rational monitoring strategies. Am J Transplant 2003;3:534-542.
,
LREFShaw LM, Holt DW, Oellerich M, et al. Current issues in therapeutic drug monitoring of mycophenolic acid: Report of a roundtable discussion. Ther Drug Monit 2001;23(4):305-315.
Cyclosporine inhibits the transport of MPAG from hepatocytes into bile, resulting in decreased enterohepatic recirculation.
LREFShaw LM, Holt DW, Oellerich M, et al. Current issues in therapeutic drug monitoring of mycophenolic acid: Report of a roundtable discussion. Ther Drug Monit 2001;23(4):305-315.
Thus, in comparison to tacrolimus coadministration, MPA plasma levels may be reduced with coadministration of cyclosporine. Due to the variability in patient plasma MPA levels, monitoring MPA levels may help to optimize outcomes in patients with high risks of organ rejection after transplantation.
LREFVan Gelder T, Meur YL, Shaw LM, et al. Therapeutic drug monitoring of mycophenolate mofetil in transplantation. Ther Drug Monit 2006;28(2):145-154.
,
LREFMeiser BM, Pfeiffer M, Schmidt D, et al. Combination therapy with tacrolimus and mycophenolate mofetil following cardiac transplantation:importance of mycophenolic acid therapeutic drug monitoring. J Heart Lung Transplant 1999;18(2):143-149.

", "Language": "en" }, { "Name": "Reagents", "Value": "

Reagents - working solutions

R1

IMPDH‑II in buffer: 15.7 U/L; IMP: 4.8 mmol/L; stabilizer; preservative

R2

NAD: 10 mmol/L in buffer; stabilizer; preservative.

R1 is in position B and R2 is in position C.

", "Language": "en" }, { "Name": "PrecautionsWarnings", "Value": "

Precautions and warnings

For in vitro diagnostic use.
Exercise the normal precautions required for handling all laboratory reagents.
Disposal of all waste material should be in accordance with local guidelines.
Safety data sheet available for professional user on request.

For USA: Caution: Federal law restricts this device to sale by or on the order of a physician.

", "Language": "en" }, { "Name": "Caution", "Value": "", "Language": "en" }, { "Name": "QualityControl", "Value": "

Quality control

For quality control, use control materials as listed in the \"Order information\" section.

In addition, other suitable control material can be used.

The control intervals and limits should be adapted to each laboratory’s individual requirements. It is recommended to perform quality control always after lot calibration and subsequently at least every 12 weeks. Values obtained should fall within the defined limits. Each laboratory should establish corrective measures to be taken if values fall outside the defined limits.

Follow the applicable government regulations and local guidelines for quality control.

", "Language": "en" }, { "Name": "SpecimenPreparation", "Value": "

Specimen collection and preparation

For specimen collection and preparation only use suitable tubes or collection containers.

Only the specimens listed below were tested and found acceptable.
Serum: Collect serum using standard sampling tubes.
Plasma: K2‑ and K3‑EDTA plasma.

The sample types listed were tested with a selection of sample collection tubes that were commercially available at the time of testing, i.e. not all available tubes of all manufacturers were tested. Sample collection systems from various manufacturers may contain differing materials which could affect the test results in some cases. When processing samples in primary tubes (sample collection systems), follow the instructions of the tube manufacturer.

Centrifuge samples containing precipitates before performing the assay.

See the limitations and interferences section for details about possible sample interferences.

Sample stability claims were established by experimental data by the manufacturer or based on reference literature and only for the temperatures/time frames as stated in the method sheet. It is the responsibility of the individual laboratory to use all available references and/or its own studies to determine specific stability criteria for its laboratory.

Specimens should be tested within 8 hours of collection if kept at room temperature. If specimens must be stored for later testing, they should be kept at 2 to 8 °C for up to 96 hours or at -20 °C or below for up to 11 months.

LREFShaw LM, Holt DW, Oellerich M, et al. Current issues in therapeutic drug monitoring of mycophenolic acid: Report of a roundtable discussion. Ther Drug Monit 2001;23(4):305-315.
,
LREFShipkova M, Armstrong VM, Schneider T, et al. Stability of mycophenolic acid glucuronide in human plasma. Clin Chem 1999;45(1):127-129.
Specimens should not be repeatedly frozen and thawed (do not exceed 5 freeze/thaw cycles).

Invert thawed specimens several times prior to testing.

", "Language": "en" } ] } }, { "ProductSpecVariant": { "MetaData": { "DocumentMaterialNumber": "0108105634190c503", "ProductName": "MPA", "ProductLongName": "Mycophenolic Acid", "Language": "en", "DocumentVersion": "4", "DocumentObjectID": "FF00000004E0AC0E", "DocumentOriginID": "FF000000049D4B0E", "MaterialNumbers": [ "08105634190" ], "InstrumentReferences": [ { "ID": "9493", "BrandName": "cobas c 303" }, { "ID": "8481", "BrandName": "cobas c 503" } ], "DisclaimerText": "Product information shown on this page contains elements of the officially released Method Sheet. If you require further information please refer to the full Method Sheet PDF under the given link, or contact your local Roche country representative." }, "Chapters": [ { "Name": "IntendedUse", "Value": "

Intended use

In vitro test for the quantitative determination of total mycophenolic acid in serum or plasma as an aid in the management of mycophenolic acid therapy in renal and cardiac transplant patients on Roche/Hitachi cobas c systems.

", "Language": "en" }, { "Name": "TestPrinciple", "Value": "

Test principle

The Roche Total MPA assay is a two‑reagent system containing IMP (inosine monophosphate), NAD (nicotinamide adenine dinucleotide), and a mutant IMPDH II (inosine monophosphate dehydrogenase) enzyme. The reagents used to measure MPA concentrations in serum or plasma mimic the in vivo mechanism of the enzyme. In vivo, IMPDH II combines with IMP and NAD to form a complex. The NAD is reduced to form NADH, and IMP is converted to XMP. The NADH leaves the enzyme first. When MPA is present, the XMP is not released from the enzyme.

In the Roche Total MPA assay, a fixed amount of mutant IMPDH in the reagent combines with fixed amounts of IMP and NAD in the reagents. The formation of NADH is measured at 340 nm. When MPA is present in the serum or plasma sample, the formation of NADH by the reagents is inhibited, as measured by a decrease in the signal at 340 nm. MPA concentration is inversely proportional to the rate of NADH formation. The reaction has been optimized for a non‑linear, six‑point calibration.

", "Language": "en" }, { "Name": "MeasuringRange", "Value": "

Limits and ranges

Measuring range

0.4‑15 µg/mL (1.2‑46.8 µmol/L)

Manually dilute samples above the measuring range with the diluent (equivalent to the 0 µg/mL calibrator) from the Roche Total MPA Calibrators (1 part sample + 4 parts diluent) and reassay. Multiply the result by 5 to obtain the specimen value.

Lower limits of measurement

Limit of Blank, Limit of Detection and Limit of Quantitation

Limit of Blank

= 0.4 µg/mL (1.2 µmol/L)

Limit of Detection

= 0.4 µg/mL (1.2 µmol/L)

Limit of Quantitation

= 0.4 µg/mL (1.2 µmol/L)

The Limit of Blank, Limit of Detection and Limit of Quantitation were determined in accordance with the CLSI (Clinical and Laboratory Standards Institute) EP17‑A2 requirements.

The Limit of Blank is the 95th percentile value from n ≥ 60 measurements of analyte‑free samples over several independent series. The Limit of Blank corresponds to the concentration below which analyte‑free samples are found with a probability of 95 %.

The Limit of Detection is determined based on the Limit of Blank and the standard deviation of low concentration samples.

The Limit of Detection corresponds to the lowest analyte concentration which can be detected (value above the Limit of Blank with a probability of 95 %).

The Limit of Quantitation is the lowest analyte concentration that can be reproducibly measured with a total error of 20 %. It has been determined using low concentration mycophenolic acid samples.

", "Language": "en" }, { "Name": "ExpectedValues", "Value": "

Expected values

The therapeutic range of mycophenolic acid is not yet fully established and is dependent on transplant type and coadministered drugs. Optimal mycophenolic acid assay values to prevent rejection may vary based on the test system and therefore should be established for each test system. Laboratories should include identification of the assay or method used in order to aid in interpretation of the results.

Optimal ranges depend on the patient’s clinical state, coadministration of other immunosuppressants, time post‑transplant and a number of other factors. Therefore, individual MPA values cannot be used as the sole indicator for making changes in treatment regimen and each patient should be thoroughly evaluated clinically before changes in treatment regimens are made.

Decreased incidences of rejection in the early months post‑transplantation have been reported in renal transplant patients with predose MPA concentrations (measured by HPLC) of ≥ 1.3 µg/mL with coadministration of cyclosporine and ≥ 1.9 µg/mL with coadministration of tacrolimus.

LREFVan Gelder T, Meur YL, Shaw LM, et al. Therapeutic drug monitoring of mycophenolate mofetil in transplantation. Ther Drug Monit 2006;28(2):145-154.
,
LREFCox VC, Ensom MHH. Mycophenolate mofetil for solid organ transplantation: Does the evidence support the need for clinical pharmacokinetic monitoring? Ther Drug Monit 2003;25(2):137-157.
An upper therapeutic range based on development of toxicity has not been established. The clinical ramifications of MPA concentrations beyond the early post transplantation periods are not yet known.
LREFVan Gelder T, Meur YL, Shaw LM, et al. Therapeutic drug monitoring of mycophenolate mofetil in transplantation. Ther Drug Monit 2006;28(2):145-154.

In cardiac transplant patients, predose MPA concentrations (measured by HPLC) of 1.2‑3.5 µg/mL have been recommended to minimize incidences of rejection.

LREFMeiser BM. Therapeutic drug monitoring of mycophenolic acid in cardiac tranplant recipients: does it make sense? Curr Opin Organ Transplant 2005;10:350-354.
,
LREFVan Gelder T, Meur YL, Shaw LM, et al. Therapeutic drug monitoring of mycophenolate mofetil in transplantation. Ther Drug Monit 2006;28(2):145-154.
Higher pre‑dose concentrations (≥ 2.5 µg/mL) in the early post‑transplantation period (< 6 months) have also been suggested.
LREFMeiser BM. Therapeutic drug monitoring of mycophenolic acid in cardiac tranplant recipients: does it make sense? Curr Opin Organ Transplant 2005;10:350-354.
,
LREFGajarski RJ, Crowley DC, Zamberlan MC, et al. Lack of correlation between MMF dose and MPA level in pediatric and young adult cardiac transplant patients: Does the MPA level matter? Am J Transplant 2004;4:1495-1500.
,
LREFMeiser BM, Reichart B. New agents and new strategies in immunosuppression after heart transplantation. Curr Opin Organ Transplant 2002;7:226-232.
Pediatric cardiac transplant patients have been shown to require higher doses of MPA in comparison to adults due to differences in MPA metabolism.
LREFMeiser BM. Therapeutic drug monitoring of mycophenolic acid in cardiac tranplant recipients: does it make sense? Curr Opin Organ Transplant 2005;10:350-354.
,
LREFGajarski RJ, Crowley DC, Zamberlan MC, et al. Lack of correlation between MMF dose and MPA level in pediatric and young adult cardiac transplant patients: Does the MPA level matter? Am J Transplant 2004;4:1495-1500.
,
LREFDipchand AI, Pietra B, McCrindle BW, et al. Mycophenolic acid levels in pediatric heart transplant recipients receiving mycophenolate mofetil. J Heart Lung Transplant 2001;20(10):1035-1043.

Each laboratory should investigate the transferability of the expected values to its own patient population and if necessary determine its own reference ranges.

", "Language": "en" }, { "Name": "LimitationInterference", "Value": "

Limitations - interference

See the Analytical specificity section of this insert for information on substances tested for cross‑reactivity in this assay. There is the possibility that other substances and/or factors may interfere with the test and cause erroneous results (e.g., technical or procedural errors). Specimens with assay values greater than the highest calibrator will be flagged by the system and must be repeated after appropriate dilution of the original sample with the zero calibrator or with the diluent from the Total MPA Calibrator kit.

Criterion: Recovery within ± 10 % of initial value at MPA concentrations of approximately 1‑5 µg/mL (3.1‑15.6 µmol/L) and 8‑12 µg/mL (25.0‑37.5 µmol/L).

Serum/Plasma

Icterus:

LREFGlick MR, Ryder KW, Jackson SA. Graphical Comparisons of Interferences in Clinical Chemistry Instrumentation. Clin Chem 1986;32:470-475.
No significant interference up to an I index of 66 for conjugated bilirubin and 17 for unconjugated bilirubin (approximate conjugated bilirubin concentration: 1129 µmol/L or 66 mg/dL; approximate unconjugated bilirubin concentration: 291 µmol/L or 17 mg/dL).

Hemolysis:

LREFGlick MR, Ryder KW, Jackson SA. Graphical Comparisons of Interferences in Clinical Chemistry Instrumentation. Clin Chem 1986;32:470-475.
No significant interference up to an H index of 1000 (approximate hemoglobin concentration: 621 µmol/L or 1000 mg/dL).

Lipemia (Intralipid):

LREFGlick MR, Ryder KW, Jackson SA. Graphical Comparisons of Interferences in Clinical Chemistry Instrumentation. Clin Chem 1986;32:470-475.
No significant interference up to an L index of 93. There is poor correlation between the L index (corresponds to turbidity) and triglycerides concentration.

Avoid the use of lipemic specimens.

Triglycerides: No significant interference from triglycerides up to a concentration of 500 mg/dL (5.65 mmol/L) with a recovery specification of ± 10 % or 600 mg/dL (6.78 mmol/L) with a recovery specification of ± 15 %.

Total protein: No significant interference from 4‑11 g/dL total protein.

Albumin: No significant interference from albumin up to a concentration of 5.4 g/dL.

Gamma globulin: No significant interference from gamma globulin up to a concentration of 6.2 g/dL.

Cholesterol: No significant interference from cholesterol up to a concentration of 350 mg/dL.

Creatinine: No significant interference from creatinine up to a concentration of 10 mg/dL.

Uric acid: No significant interference from uric acid up to a concentration of 20 mg/dL.

There is the possibility that other substances and/or factors may interfere with the test and cause unreliable results.

In very rare cases, gammopathy, in particular type IgM (Waldenström’s macroglobulinemia), may cause unreliable results.

LREFBakker AJ, Mücke M. Gammopathy interference in clinical chemistry assays: mechanisms, detection and prevention. Clin Chem Lab Med 2007;45(9):1240-1243.

For diagnostic purposes, the results should always be assessed in conjunction with the patient’s medical history, clinical examination and other findings.

ACTION REQUIRED
Special Wash Programming: The use of special wash steps is mandatory when certain test combinations are run together oncobas c systems. All special wash programming necessary for avoiding carry‑over is available via the cobas link. The latest version of the carry‑over evasion list can be found with the NaOHD/SMS/SCCS Method Sheet for information. For further instructions refer to the operator’s manual.

", "Language": "en" }, { "Name": "OrderInformation", "Value": "

OrderInformation (CC Reagents - cobas + Integra)

Order information

Analyzer(s) on which cobas c pack(s) can be used

08105634190

Mycophenolic Acid (100 tests)

System‑ID 2090 001

cobas c 303, cobas c 503

Materials required (but not provided):

04357221190

Total MPA Calibrators
A‑F (1 x 5 mL)
Diluent (1 x 10 mL)

System‑ID 07 6824 3
Codes 20490‑20495

04357230190

Total MPA Controls
Level I (2 x 5 mL)
Level II (2 x 5 mL)
Level III (2 x 5 mL)


Code 20107
Code 20108
Code 20109

", "Language": "en" }, { "Name": "SystemInformation", "Value": "

System information

MPA: ACN 20900

", "Language": "en" }, { "Name": "Handling", "Value": "

Reagent handling

Ready for use

", "Language": "en" }, { "Name": "TestDefinition", "Value": "

Application for serum and plasma

Test definition

Reporting time

10 min

Wavelength (sub/main)

415/340 nm

Reagent pipetting

Diluent (H2O)

R1

132 µL

R2

14 µL

15 µL

Sample volumes

Sample

Sample dilution

Sample

Diluent (NaCl)

Normal

2.2 µL

Decreased

2.2 µL

Increased

2.2 µL

For further information about the assay test definitions refer to the application parameters setting screen of the corresponding analyzer and assay.

", "Language": "en" }, { "Name": "StorageStability", "Value": "

Storage and stability

Shelf life at 2‑8 °C:

See expiration date on cobas c pack label

On‑board in use and refrigerated on the analyzer:

Do not freeze.

12 weeks

", "Language": "en" }, { "Name": "Calibration", "Value": "

Calibration

Calibrators

S1‑6: Total MPA Calibrators

Calibration mode

Non‑linear

Calibration frequency

Full calibration
- after reagent lot change and every 2 weeks
- as required following quality control procedures

Calibration interval may be extended based on acceptable verification of calibration by the laboratory.

Traceability: The Total MPA Calibrators are prepared to contain known quantities of mycophenolic acid in normal human serum and are traceable to a primary reference method (HPLC).

LREFBrandhorst G, Streit F, Goetze S, et al. Quantification by liquid chromatography tandem mass spectrometry of mycophenolic acid and its phenol and acyl glucuronide metabolites. Clin Chem 2006;52:1962-1964.

", "Language": "en" }, { "Name": "Limitations", "Value": "", "Language": "en" }, { "Name": "PerformanceData", "Value": "

Specific performance data

Representative performance data on the analyzers are given below. These data represent the performance of the analytical procedure itself.

Results obtained in individual laboratories may differ due to heterogenous sample materials, aging of analyzer components and mixture of reagents running on the analyzer.

", "Language": "en" }, { "Name": "Precision", "Value": "

Precision

Precision was determined using human samples and controls in accordance with the CLSI (Clinical and Laboratory Standards Institute) EP05‑A3 requirements with repeatability (n = 84) and intermediate precision (2 aliquots per run, 2 runs per day, 21 days). Results for repeatability and intermediate precision were obtained on the cobas c 503 analyzer.

Serum/Plasma

Repeatability

Mean

SD

CV

µg/mL

µg/mL

%

TMPA 1a)

0.893

0.0120

1.3

TMPA 2b)

3.47

0.0189

0.5

TMPA 3c)

11.8

0.0951

0.8

Human serum 1

0.851

0.0144

1.7

Human serum 2

1.47

0.0146

1.0

Human serum 3

2.11

0.0150

0.7

Human serum 4

8.27

0.0600

0.7

Human serum 5

14.1

0.149

1.1

Intermediate precision

Mean

SD

CV

µg/mL

µg/mL

%

TMPA 1

FREFTotal MPA Control Level I

0.901

0.0190

2.1

TMPA 2

FREFTotal MPA Control Level II

3.46

0.0303

0.9

TMPA 3

FREFTotal MPA Control Level III

11.8

0.106

0.9

Human serum 1

0.851

0.0216

2.5

Human serum 2

1.47

0.0227

1.5

Human serum 3

2.12

0.0264

1.2

Human serum 4

8.33

0.0748

0.9

Human serum 5

14.1

0.197

1.4

The data obtained on cobas c 503 analyzer(s) are representative for cobas c 303 analyzer(s).

", "Language": "en" }, { "Name": "MethodComparison", "Value": "

Method comparison

Mycophenolic acid values for human serum and plasma samples obtained on a cobas c 503 analyzer (y) were compared with those determined using the corresponding reagent on a cobas c 501 analyzer (x).

Serum/plasma

Sample size (n) = 74

Passing/Bablok

LREFBablok W, Passing H, Bender R, et al. A general regression procedure for method transformation. Application of linear regression procedures for method comparison studies in clinical chemistry, Part III. J Clin Chem Clin Biochem 1988 Nov;26(11):783-790.

Linear regression

y = 0.995x + 0.00222

y = 0.998x - 0.0186

τ = 0.994

r = 1.000

The sample concentrations were between 0.620 and 14.5 µg/mL.

Mycophenolic acid values for human serum and plasma samples obtained on a cobas c 303 analyzer (y) were compared with those determined using the corresponding reagent on a cobas c 501 analyzer (x).

Sample size (n) = 74

Passing/Bablok

LREFBablok W, Passing H, Bender R, et al. A general regression procedure for method transformation. Application of linear regression procedures for method comparison studies in clinical chemistry, Part III. J Clin Chem Clin Biochem 1988 Nov;26(11):783-790.

Linear regression

y = 0.975x - 0.0146

y = 0.974x - 0.0165

τ = 0.991

r = 1.000

The sample concentrations were between 0.580 and 14.9 µg/mL.

", "Language": "en" }, { "Name": "Summary", "Value": "

Summary

Mycophenolic acid is prescribed as mycophenolate mofetil (MMF), a morpholino ester, or as mycophenolate sodium. The MMF prodrug is rapidly metabolized to the active compound, MPA, via cleavage of the ester linkage.

LREFWeber LT, Shipkova M, Armstrong VW, et al. The pharmacokinetic-pharmacodynamic relationship for total and free mycophenolic acid in pediatric renal transplant recipients: A report of the German study group on mycophenolate mofetil therapy. J Am Soc Nephrol 2002;13:759-768.
MPA inhibits de novo purine biosynthesis by the reversible, noncompetitive inhibition of inosine monophosphate dehydrogenase (IMPDH‑II).
LREFWeber LT, Shipkova M, Armstrong VW, et al. The pharmacokinetic-pharmacodynamic relationship for total and free mycophenolic acid in pediatric renal transplant recipients: A report of the German study group on mycophenolate mofetil therapy. J Am Soc Nephrol 2002;13:759-768.
,
LREFShaw LM, Nichols A, Hale M, et al. Therapeutic monitoring of mycophenolic acid: A consensus panel report. Clin Biochem 1998;31(5):317-322.
The inhibition of IMPDH‑II in activated lymphocytes reduces intracellular guanine nucleotide pools, thus arresting lymphocyte proliferation.
LREFWu JC. Mycophenolate mofetil: molecular mechanism of action. Perspect Drug Discovery Design 1994;2:185-204.
,
LREFRansom JT. The mechanism of action of mycophenolate mofetil. Ther Drug Monit 1995;17:681-684.

MPA is metabolized in the liver by glucuronidation at the phenolic hydroxyl group to the pharmacologically inactive mycophenolic acid glucuronide (MPAG). Plasma levels of MPAG are approximately 40‑fold higher than those of the parent drug.

LREFSchutz E, Shikova M, Armstrong VW, et al. Therapeutic drug monitoring of mycophenolic acid: comparison of HPLC and immunoassay reveals new metabolites. Transplant Proc 1998;30:1185-1187.
,
LREFIndjova D, Kassabova L, Svinarov D. Simultaneous determination of mycophenolic acid and its phenolic glucuronide in human plasma using an isocratic high-performance liquid chromatography procedure. J Chromatogr B Analyt Technol Biomed Life Sci 2005 Mar 25;817(2):327-330.
In addition to the primary metabolite, two additional metabolites of MPA have been identified, the acyl glucuronide (Ac‑MPAG) and the phenolic glucoside of MPA. Of these two, only the acyl glucuronide is able to inhibit IMPDH‑II in vitro.
LREFWeber LT, Shipkova M, Armstrong VW, et al. The pharmacokinetic-pharmacodynamic relationship for total and free mycophenolic acid in pediatric renal transplant recipients: A report of the German study group on mycophenolate mofetil therapy. J Am Soc Nephrol 2002;13:759-768.

Growing clinical evidence indicates that therapeutic drug monitoring of MPA can maximize the therapeutic benefit of the drug and minimize its adverse effects.

LREFMeiser BM. Therapeutic drug monitoring of mycophenolic acid in cardiac tranplant recipients: does it make sense? Curr Opin Organ Transplant 2005;10:350-354.
,
LREFGajarski RJ, Crowley DC, Zamberlan MC, et al. Lack of correlation between MMF dose and MPA level in pediatric and young adult cardiac transplant patients: Does the MPA level matter? Am J Transplant 2004;4:1495-1500.
,
LREFDipchand AI, Pietra B, McCrindle BW, et al. Mycophenolic acid levels in pediatric heart transplant recipients receiving mycophenolate mofetil. J Heart Lung Transplant 2001;20(10):1035-1043.
,
LREFKuypers DRJ. Immunosuppressive drug monitoring- What to use in clinical practice today to improve renal graft outcome? Transplant International 2005;18:140-150.
,
LREFHessilink DA, van Gelder T. The influence of cyclosporine on mycophenolic acid plasma concentrations: A review. Transplant Rev 2003;17(3):158-163.
It is generally co‑administered with calcineurin inhibitors (cyclosporine or tacrolimus) and, more recently, other immunosuppressants including sirolimus.
LREFMeiser BM. Therapeutic drug monitoring of mycophenolic acid in cardiac tranplant recipients: does it make sense? Curr Opin Organ Transplant 2005;10:350-354.
,
LREFVan Gelder T, Meur YL, Shaw LM, et al. Therapeutic drug monitoring of mycophenolate mofetil in transplantation. Ther Drug Monit 2006;28(2):145-154.

Peak levels of MPA in plasma occur approximately 1 to 2 hours after oral dosing. A secondary peak then occurs 6 to 12 hours after dosing due to enterohepatic recirculation of the drug. The pharmacokinetics of MPA exhibit wide between‑patient variability and may be altered in specific patient populations due to concomitant disease states or interactions with other immunosuppressants.

LREFCox VC, Ensom MHH. Mycophenolate mofetil for solid organ transplantation: Does the evidence support the need for clinical pharmacokinetic monitoring? Ther Drug Monit 2003;25(2):137-157.
,
LREFShaw LM, Korecka M, Venkataramanan R, et al. Mycophenolic acid pharmacodynamics and pharmacokinetics provide a basis for rational monitoring strategies. Am J Transplant 2003;3:534-542.
,
LREFShaw LM, Holt DW, Oellerich M, et al. Current issues in therapeutic drug monitoring of mycophenolic acid: Report of a roundtable discussion. Ther Drug Monit 2001;23(4):305-315.
Cyclosporine inhibits the transport of MPAG from hepatocytes into bile, resulting in decreased enterohepatic recirculation.
LREFShaw LM, Holt DW, Oellerich M, et al. Current issues in therapeutic drug monitoring of mycophenolic acid: Report of a roundtable discussion. Ther Drug Monit 2001;23(4):305-315.
Thus, in comparison to tacrolimus coadministration, MPA plasma levels may be reduced with coadministration of cyclosporine. Due to the variability in patient plasma MPA levels, monitoring MPA levels may help to optimize outcomes in patients with high risks of organ rejection after transplantation.
LREFVan Gelder T, Meur YL, Shaw LM, et al. Therapeutic drug monitoring of mycophenolate mofetil in transplantation. Ther Drug Monit 2006;28(2):145-154.
,
LREFMeiser BM, Pfeiffer M, Schmidt D, et al. Combination therapy with tacrolimus and mycophenolate mofetil following cardiac transplantation:importance of mycophenolic acid therapeutic drug monitoring. J Heart Lung Transplant 1999;18(2):143-149.

", "Language": "en" }, { "Name": "Reagents", "Value": "

Reagents - working solutions

R1

IMPDH‑II in buffer: 15.7 U/L; IMP: 4.8 mmol/L; stabilizer; preservative

R2

NAD: 10 mmol/L in buffer; stabilizer; preservative.

R1 is in position B and R2 is in position C.

", "Language": "en" }, { "Name": "PrecautionsWarnings", "Value": "

Precautions and warnings

For in vitro diagnostic use for health care professionals. Exercise the normal precautions required for handling all laboratory reagents.

Infectious or microbial waste:
Warning: handle waste as potentially biohazardous material. Dispose of waste according to accepted laboratory instructions and procedures.

Environmental hazards:
Apply all relevant local disposal regulations to determine the safe disposal.

Safety data sheet available for professional user on request.

", "Language": "en" }, { "Name": "Caution", "Value": "", "Language": "en" }, { "Name": "QualityControl", "Value": "

Quality control

For quality control, use control materials as listed in the “Order information” section. In addition, other suitable control material can be used.

The control intervals and limits should be adapted to each laboratory’s individual requirements. It is recommended to perform quality control always after lot calibration and subsequently at least every 12 weeks.

Values obtained should fall within the defined limits. Each laboratory should establish corrective measures to be taken if values fall outside the defined limits.

Follow the applicable government regulations and local guidelines for quality control.

", "Language": "en" }, { "Name": "SpecimenPreparation", "Value": "

Specimen collection and preparation

For specimen collection and preparation only use suitable tubes or collection containers.

Only the specimens listed below were tested and found acceptable.
Serum: Collect serum using standard sampling tubes.
Plasma: K2‑ and K3‑EDTA plasma.

The sample types listed were tested with a selection of sample collection tubes that were commercially available at the time of testing, i.e. not all available tubes of all manufacturers were tested. Sample collection systems from various manufacturers may contain differing materials which could affect the test results in some cases. When processing samples in primary tubes (sample collection systems), follow the instructions of the tube manufacturer.

Centrifuge samples containing precipitates before performing the assay.

See the limitations and interferences section for details about possible sample interferences.

Sample stability claims were established by experimental data by the manufacturer or based on reference literature and only for the temperatures/time frames as stated in the method sheet. It is the responsibility of the individual laboratory to use all available references and/or its own studies to determine specific stability criteria for its laboratory.

Specimens should be tested within 8 hours of collection if kept at room temperature. If specimens must be stored for later testing, they should be kept at 2 to 8 °C for up to 96 hours or at -20 °C or below for up to 11 months.

LREFShaw LM, Holt DW, Oellerich M, et al. Current issues in therapeutic drug monitoring of mycophenolic acid: Report of a roundtable discussion. Ther Drug Monit 2001;23(4):305-315.
,
LREFShipkova M, Armstrong VM, Schneider T, et al. Stability of mycophenolic acid glucuronide in human plasma. Clin Chem 1999;45(1):127-129.
Specimens should not be repeatedly frozen and thawed (do not exceed 5 freeze/thaw cycles).

Invert thawed specimens several times prior to testing.

", "Language": "en" } ] } }, { "ProductSpecVariant": { "MetaData": { "DocumentMaterialNumber": "0108105634190c503", "ProductName": "MPA", "ProductLongName": "Mycophenolic Acid", "Language": "en", "DocumentVersion": "5", "DocumentObjectID": "FF0000000585320E", "DocumentOriginID": "FF000000049D4C0E", "MaterialNumbers": [ "08105634190" ], "InstrumentReferences": [ { "ID": "9493", "BrandName": "cobas c 303" }, { "ID": "8481", "BrandName": "cobas c 503" } ], "DisclaimerText": "Product information shown on this page contains elements of the officially released Method Sheet. If you require further information please refer to the full Method Sheet PDF under the given link, or contact your local Roche country representative." }, "Chapters": [ { "Name": "IntendedUse", "Value": "

Intended use

In vitro test for the quantitative determination of total mycophenolic acid in serum or plasma as an aid in the management of mycophenolic acid therapy in renal and cardiac transplant patients on Roche/Hitachi cobas c systems.

", "Language": "en" }, { "Name": "TestPrinciple", "Value": "

Test principle

The Roche Total MPA assay is a two‑reagent system containing IMP (inosine monophosphate), NAD (nicotinamide adenine dinucleotide), and a mutant IMPDH II (inosine monophosphate dehydrogenase) enzyme. The reagents used to measure MPA concentrations in serum or plasma mimic the in vivo mechanism of the enzyme. In vivo, IMPDH II combines with IMP and NAD to form a complex. The NAD is reduced to form NADH, and IMP is converted to XMP. The NADH leaves the enzyme first. When MPA is present, the XMP is not released from the enzyme.

In the Roche Total MPA assay, a fixed amount of mutant IMPDH in the reagent combines with fixed amounts of IMP and NAD in the reagents. The formation of NADH is measured at 340 nm. When MPA is present in the serum or plasma sample, the formation of NADH by the reagents is inhibited, as measured by a decrease in the signal at 340 nm. MPA concentration is inversely proportional to the rate of NADH formation. The reaction has been optimized for a non‑linear, six‑point calibration.

", "Language": "en" }, { "Name": "MeasuringRange", "Value": "

Limits and ranges

Measuring range

0.4‑15 µg/mL (1.2‑46.8 µmol/L)

Manually dilute samples above the measuring range with the diluent (equivalent to the 0 µg/mL calibrator) from the Roche Total MPA Calibrators (1 part sample + 4 parts diluent) and reassay. Multiply the result by 5 to obtain the specimen value.

Lower limits of measurement

Limit of Blank, Limit of Detection and Limit of Quantitation

Limit of Blank

= 0.4 µg/mL (1.2 µmol/L)

Limit of Detection

= 0.4 µg/mL (1.2 µmol/L)

Limit of Quantitation

= 0.4 µg/mL (1.2 µmol/L)

The Limit of Blank, Limit of Detection and Limit of Quantitation were determined in accordance with the CLSI (Clinical and Laboratory Standards Institute) EP17‑A2 requirements.

The Limit of Blank is the 95th percentile value from n ≥ 60 measurements of analyte‑free samples over several independent series. The Limit of Blank corresponds to the concentration below which analyte‑free samples are found with a probability of 95 %.

The Limit of Detection is determined based on the Limit of Blank and the standard deviation of low concentration samples.

The Limit of Detection corresponds to the lowest analyte concentration which can be detected (value above the Limit of Blank with a probability of 95 %).

The Limit of Quantitation is the lowest analyte concentration that can be reproducibly measured with a total error of 20 %. It has been determined using low concentration mycophenolic acid samples.

", "Language": "en" }, { "Name": "ExpectedValues", "Value": "

Expected values

The therapeutic range of mycophenolic acid is not yet fully established and is dependent on transplant type and coadministered drugs. Optimal mycophenolic acid assay values to prevent rejection may vary based on the test system and therefore should be established for each test system. Laboratories should include identification of the assay or method used in order to aid in interpretation of the results.

Optimal ranges depend on the patient’s clinical state, coadministration of other immunosuppressants, time post‑transplant and a number of other factors. Therefore, individual MPA values cannot be used as the sole indicator for making changes in treatment regimen and each patient should be thoroughly evaluated clinically before changes in treatment regimens are made.

Decreased incidences of rejection in the early months post‑transplantation have been reported in renal transplant patients with predose MPA concentrations (measured by HPLC) of ≥ 1.3 µg/mL with coadministration of cyclosporine and ≥ 1.9 µg/mL with coadministration of tacrolimus.

LREFVan Gelder T, Meur YL, Shaw LM, et al. Therapeutic drug monitoring of mycophenolate mofetil in transplantation. Ther Drug Monit 2006;28(2):145-154.
,
LREFCox VC, Ensom MHH. Mycophenolate mofetil for solid organ transplantation: Does the evidence support the need for clinical pharmacokinetic monitoring? Ther Drug Monit 2003;25(2):137-157.
An upper therapeutic range based on development of toxicity has not been established. The clinical ramifications of MPA concentrations beyond the early post transplantation periods are not yet known.
LREFVan Gelder T, Meur YL, Shaw LM, et al. Therapeutic drug monitoring of mycophenolate mofetil in transplantation. Ther Drug Monit 2006;28(2):145-154.

In cardiac transplant patients, predose MPA concentrations (measured by HPLC) of 1.2‑3.5 µg/mL have been recommended to minimize incidences of rejection.

LREFMeiser BM. Therapeutic drug monitoring of mycophenolic acid in cardiac tranplant recipients: does it make sense? Curr Opin Organ Transplant 2005;10:350-354.
,
LREFVan Gelder T, Meur YL, Shaw LM, et al. Therapeutic drug monitoring of mycophenolate mofetil in transplantation. Ther Drug Monit 2006;28(2):145-154.
Higher pre‑dose concentrations (≥ 2.5 µg/mL) in the early post‑transplantation period (< 6 months) have also been suggested.
LREFMeiser BM. Therapeutic drug monitoring of mycophenolic acid in cardiac tranplant recipients: does it make sense? Curr Opin Organ Transplant 2005;10:350-354.
,
LREFGajarski RJ, Crowley DC, Zamberlan MC, et al. Lack of correlation between MMF dose and MPA level in pediatric and young adult cardiac transplant patients: Does the MPA level matter? Am J Transplant 2004;4:1495-1500.
,
LREFMeiser BM, Reichart B. New agents and new strategies in immunosuppression after heart transplantation. Curr Opin Organ Transplant 2002;7:226-232.
Pediatric cardiac transplant patients have been shown to require higher doses of MPA in comparison to adults due to differences in MPA metabolism.
LREFMeiser BM. Therapeutic drug monitoring of mycophenolic acid in cardiac tranplant recipients: does it make sense? Curr Opin Organ Transplant 2005;10:350-354.
,
LREFGajarski RJ, Crowley DC, Zamberlan MC, et al. Lack of correlation between MMF dose and MPA level in pediatric and young adult cardiac transplant patients: Does the MPA level matter? Am J Transplant 2004;4:1495-1500.
,
LREFDipchand AI, Pietra B, McCrindle BW, et al. Mycophenolic acid levels in pediatric heart transplant recipients receiving mycophenolate mofetil. J Heart Lung Transplant 2001;20(10):1035-1043.

Each laboratory should investigate the transferability of the expected values to its own patient population and if necessary determine its own reference ranges.

", "Language": "en" }, { "Name": "LimitationInterference", "Value": "

Limitations - interference

See the Analytical specificity section of this insert for information on substances tested for cross‑reactivity in this assay. There is the possibility that other substances and/or factors may interfere with the test and cause erroneous results (e.g., technical or procedural errors). Specimens with assay values greater than the highest calibrator will be flagged by the system and must be repeated after appropriate dilution of the original sample with the zero calibrator or with the diluent from the Total MPA Calibrator kit.

Criterion: Recovery within ± 10 % of initial value at MPA concentrations of approximately 1‑5 µg/mL (3.1‑15.6 µmol/L) and 8‑12 µg/mL (25.0‑37.5 µmol/L).

Serum/Plasma

Icterus:

LREFGlick MR, Ryder KW, Jackson SA. Graphical Comparisons of Interferences in Clinical Chemistry Instrumentation. Clin Chem 1986;32:470-475.
No significant interference up to an I index of 66 for conjugated bilirubin and 17 for unconjugated bilirubin (approximate conjugated bilirubin concentration: 1129 µmol/L or 66 mg/dL; approximate unconjugated bilirubin concentration: 291 µmol/L or 17 mg/dL).

Hemolysis:

LREFGlick MR, Ryder KW, Jackson SA. Graphical Comparisons of Interferences in Clinical Chemistry Instrumentation. Clin Chem 1986;32:470-475.
No significant interference up to an H index of 1000 (approximate hemoglobin concentration: 621 µmol/L or 1000 mg/dL).

Lipemia (Intralipid):

LREFGlick MR, Ryder KW, Jackson SA. Graphical Comparisons of Interferences in Clinical Chemistry Instrumentation. Clin Chem 1986;32:470-475.
No significant interference up to an L index of 93. There is poor correlation between the L index (corresponds to turbidity) and triglycerides concentration.

Avoid the use of lipemic specimens.

Triglycerides: No significant interference from triglycerides up to a concentration of 500 mg/dL (5.65 mmol/L) with a recovery specification of ± 10 % or 600 mg/dL (6.78 mmol/L) with a recovery specification of ± 15 %.

Total protein: No significant interference from 4‑11 g/dL total protein.

Albumin: No significant interference from albumin up to a concentration of 5.4 g/dL.

Gamma globulin: No significant interference from gamma globulin up to a concentration of 6.2 g/dL.

Cholesterol: No significant interference from cholesterol up to a concentration of 350 mg/dL.

Creatinine: No significant interference from creatinine up to a concentration of 10 mg/dL.

Uric acid: No significant interference from uric acid up to a concentration of 20 mg/dL.

There is the possibility that other substances and/or factors may interfere with the test and cause unreliable results.

In very rare cases, gammopathy, in particular type IgM (Waldenström’s macroglobulinemia), may cause unreliable results.

LREFBakker AJ, Mücke M. Gammopathy interference in clinical chemistry assays: mechanisms, detection and prevention. Clin Chem Lab Med 2007;45(9):1240-1243.

For diagnostic purposes, the results should always be assessed in conjunction with the patient’s medical history, clinical examination and other findings.

ACTION REQUIRED
Special Wash Programming: The use of special wash steps is mandatory when certain test combinations are run together on cobas c systems. All special wash programming necessary for avoiding carry‑over is available via the cobas link. The latest version of the carry‑over evasion list can be found with the NaOHD/SMS/SCCS Method Sheet for information. For further instructions refer to the operator’s manual.

", "Language": "en" }, { "Name": "OrderInformation", "Value": "

OrderInformation (CC Reagents - cobas + Integra)

Order information

Analyzer(s) on which cobas c pack(s) can be used

08105634190

Mycophenolic Acid (100 tests)

System‑ID 2090 001

cobas c 303, cobas c 503

Materials required (but not provided):

04357221190

Total MPA Calibrators
A‑F (1 x 5 mL)
Diluent (1 x 10 mL)

System‑ID 07 6824 3
Codes 20490‑20495

04357230190

Total MPA Controls
Level I (2 x 5 mL)
Level II (2 x 5 mL)
Level III (2 x 5 mL)


Code 20107
Code 20108
Code 20109

", "Language": "en" }, { "Name": "SystemInformation", "Value": "

System information

MPA: ACN 20900

", "Language": "en" }, { "Name": "Handling", "Value": "

Reagent handling

Ready for use

", "Language": "en" }, { "Name": "TestDefinition", "Value": "

Application for serum and plasma

Test definition

Reporting time

10 min

Wavelength (sub/main)

415/340 nm

Reagent pipetting

Diluent (H2O)

R1

132 µL

R2

14 µL

15 µL

Sample volumes

Sample

Sample dilution

Sample

Diluent (NaCl)

Normal

2.2 µL

Decreased

2.2 µL

Increased

2.2 µL

For further information about the assay test definitions refer to the application parameters setting screen of the corresponding analyzer and assay.

", "Language": "en" }, { "Name": "StorageStability", "Value": "

Storage and stability

Shelf life at 2‑8 °C:

See expiration date on cobas c pack label

On‑board in use and refrigerated on the analyzer:

Do not freeze.

12 weeks

", "Language": "en" }, { "Name": "Calibration", "Value": "

Calibration

Calibrators

S1‑6: Total MPA Calibrators

Calibration mode

Non‑linear

Calibration frequency

Full calibration
- after reagent lot change and every 2 weeks
- as required following quality control procedures

Calibration interval may be extended based on acceptable verification of calibration by the laboratory.

Traceability: The Total MPA Calibrators are prepared to contain known quantities of mycophenolic acid in normal human serum and are traceable to a primary reference method (HPLC).

LREFBrandhorst G, Streit F, Goetze S, et al. Quantification by liquid chromatography tandem mass spectrometry of mycophenolic acid and its phenol and acyl glucuronide metabolites. Clin Chem 2006;52:1962-1964.

", "Language": "en" }, { "Name": "Limitations", "Value": "", "Language": "en" }, { "Name": "PerformanceData", "Value": "

Specific performance data

Representative performance data on the analyzers are given below. These data represent the performance of the analytical procedure itself.

Results obtained in individual laboratories may differ due to heterogenous sample materials, aging of analyzer components and mixture of reagents running on the analyzer.

", "Language": "en" }, { "Name": "Precision", "Value": "

Precision

Precision was determined using human samples and controls in accordance with the CLSI (Clinical and Laboratory Standards Institute) EP05‑A3 requirements with repeatability (n = 84) and intermediate precision (2 aliquots per run, 2 runs per day, 21 days). Results for repeatability and intermediate precision were obtained on the cobas c 503 analyzer.

Serum/Plasma

Repeatability

Mean

SD

CV

µg/mL

µg/mL

%

TMPA 1a)

0.893

0.0120

1.3

TMPA 2b)

3.47

0.0189

0.5

TMPA 3c)

11.8

0.0951

0.8

Human serum 1

0.851

0.0144

1.7

Human serum 2

1.47

0.0146

1.0

Human serum 3

2.11

0.0150

0.7

Human serum 4

8.27

0.0600

0.7

Human serum 5

14.1

0.149

1.1

Intermediate precision

Mean

SD

CV

µg/mL

µg/mL

%

TMPA 1

FREFTotal MPA Control Level I

0.901

0.0190

2.1

TMPA 2

FREFTotal MPA Control Level II

3.46

0.0303

0.9

TMPA 3

FREFTotal MPA Control Level III

11.8

0.106

0.9

Human serum 1

0.851

0.0216

2.5

Human serum 2

1.47

0.0227

1.5

Human serum 3

2.12

0.0264

1.2

Human serum 4

8.33

0.0748

0.9

Human serum 5

14.1

0.197

1.4

The data obtained on cobas c 503 analyzer(s) are representative for cobas c 303 analyzer(s).

", "Language": "en" }, { "Name": "MethodComparison", "Value": "

Method comparison

Mycophenolic acid values for human serum and plasma samples obtained on a cobas c 503 analyzer (y) were compared with those determined using the corresponding reagent on a cobas c 501 analyzer (x).

Serum/plasma

Sample size (n) = 74

Passing/Bablok

LREFBablok W, Passing H, Bender R, et al. A general regression procedure for method transformation. Application of linear regression procedures for method comparison studies in clinical chemistry, Part III. J Clin Chem Clin Biochem 1988 Nov;26(11):783-790.

Linear regression

y = 0.995x + 0.00222

y = 0.998x - 0.0186

τ = 0.994

r = 1.000

The sample concentrations were between 0.620 and 14.5 µg/mL.

Mycophenolic acid values for human serum and plasma samples obtained on a cobas c 303 analyzer (y) were compared with those determined using the corresponding reagent on a cobas c 501 analyzer (x).

Sample size (n) = 74

Passing/Bablok

LREFBablok W, Passing H, Bender R, et al. A general regression procedure for method transformation. Application of linear regression procedures for method comparison studies in clinical chemistry, Part III. J Clin Chem Clin Biochem 1988 Nov;26(11):783-790.

Linear regression

y = 0.975x - 0.0146

y = 0.974x - 0.0165

τ = 0.991

r = 1.000

The sample concentrations were between 0.580 and 14.9 µg/mL.

", "Language": "en" }, { "Name": "Summary", "Value": "

Summary

Mycophenolic acid is prescribed as mycophenolate mofetil (MMF), a morpholino ester, or as mycophenolate sodium. The MMF prodrug is rapidly metabolized to the active compound, MPA, via cleavage of the ester linkage.

LREFWeber LT, Shipkova M, Armstrong VW, et al. The pharmacokinetic-pharmacodynamic relationship for total and free mycophenolic acid in pediatric renal transplant recipients: A report of the German study group on mycophenolate mofetil therapy. J Am Soc Nephrol 2002;13:759-768.
MPA inhibits de novo purine biosynthesis by the reversible, noncompetitive inhibition of inosine monophosphate dehydrogenase (IMPDH‑II).
LREFWeber LT, Shipkova M, Armstrong VW, et al. The pharmacokinetic-pharmacodynamic relationship for total and free mycophenolic acid in pediatric renal transplant recipients: A report of the German study group on mycophenolate mofetil therapy. J Am Soc Nephrol 2002;13:759-768.
,
LREFShaw LM, Nichols A, Hale M, et al. Therapeutic monitoring of mycophenolic acid: A consensus panel report. Clin Biochem 1998;31(5):317-322.
The inhibition of IMPDH‑II in activated lymphocytes reduces intracellular guanine nucleotide pools, thus arresting lymphocyte proliferation.
LREFWu JC. Mycophenolate mofetil: molecular mechanism of action. Perspect Drug Discovery Design 1994;2:185-204.
,
LREFRansom JT. The mechanism of action of mycophenolate mofetil. Ther Drug Monit 1995;17:681-684.

MPA is metabolized in the liver by glucuronidation at the phenolic hydroxyl group to the pharmacologically inactive mycophenolic acid glucuronide (MPAG). Plasma levels of MPAG are approximately 40‑fold higher than those of the parent drug.

LREFSchutz E, Shikova M, Armstrong VW, et al. Therapeutic drug monitoring of mycophenolic acid: comparison of HPLC and immunoassay reveals new metabolites. Transplant Proc 1998;30:1185-1187.
,
LREFIndjova D, Kassabova L, Svinarov D. Simultaneous determination of mycophenolic acid and its phenolic glucuronide in human plasma using an isocratic high-performance liquid chromatography procedure. J Chromatogr B Analyt Technol Biomed Life Sci 2005 Mar 25;817(2):327-330.
In addition to the primary metabolite, two additional metabolites of MPA have been identified, the acyl glucuronide (Ac‑MPAG) and the phenolic glucoside of MPA. Of these two, only the acyl glucuronide is able to inhibit IMPDH‑II in vitro.
LREFWeber LT, Shipkova M, Armstrong VW, et al. The pharmacokinetic-pharmacodynamic relationship for total and free mycophenolic acid in pediatric renal transplant recipients: A report of the German study group on mycophenolate mofetil therapy. J Am Soc Nephrol 2002;13:759-768.

Growing clinical evidence indicates that therapeutic drug monitoring of MPA can maximize the therapeutic benefit of the drug and minimize its adverse effects.

LREFMeiser BM. Therapeutic drug monitoring of mycophenolic acid in cardiac tranplant recipients: does it make sense? Curr Opin Organ Transplant 2005;10:350-354.
,
LREFGajarski RJ, Crowley DC, Zamberlan MC, et al. Lack of correlation between MMF dose and MPA level in pediatric and young adult cardiac transplant patients: Does the MPA level matter? Am J Transplant 2004;4:1495-1500.
,
LREFDipchand AI, Pietra B, McCrindle BW, et al. Mycophenolic acid levels in pediatric heart transplant recipients receiving mycophenolate mofetil. J Heart Lung Transplant 2001;20(10):1035-1043.
,
LREFKuypers DRJ. Immunosuppressive drug monitoring- What to use in clinical practice today to improve renal graft outcome? Transplant International 2005;18:140-150.
,
LREFHessilink DA, van Gelder T. The influence of cyclosporine on mycophenolic acid plasma concentrations: A review. Transplant Rev 2003;17(3):158-163.
It is generally co‑administered with calcineurin inhibitors (cyclosporine or tacrolimus) and, more recently, other immunosuppressants including sirolimus.
LREFMeiser BM. Therapeutic drug monitoring of mycophenolic acid in cardiac tranplant recipients: does it make sense? Curr Opin Organ Transplant 2005;10:350-354.
,
LREFVan Gelder T, Meur YL, Shaw LM, et al. Therapeutic drug monitoring of mycophenolate mofetil in transplantation. Ther Drug Monit 2006;28(2):145-154.

Peak levels of MPA in plasma occur approximately 1 to 2 hours after oral dosing. A secondary peak then occurs 6 to 12 hours after dosing due to enterohepatic recirculation of the drug. The pharmacokinetics of MPA exhibit wide between‑patient variability and may be altered in specific patient populations due to concomitant disease states or interactions with other immunosuppressants.

LREFCox VC, Ensom MHH. Mycophenolate mofetil for solid organ transplantation: Does the evidence support the need for clinical pharmacokinetic monitoring? Ther Drug Monit 2003;25(2):137-157.
,
LREFShaw LM, Korecka M, Venkataramanan R, et al. Mycophenolic acid pharmacodynamics and pharmacokinetics provide a basis for rational monitoring strategies. Am J Transplant 2003;3:534-542.
,
LREFShaw LM, Holt DW, Oellerich M, et al. Current issues in therapeutic drug monitoring of mycophenolic acid: Report of a roundtable discussion. Ther Drug Monit 2001;23(4):305-315.
Cyclosporine inhibits the transport of MPAG from hepatocytes into bile, resulting in decreased enterohepatic recirculation.
LREFShaw LM, Holt DW, Oellerich M, et al. Current issues in therapeutic drug monitoring of mycophenolic acid: Report of a roundtable discussion. Ther Drug Monit 2001;23(4):305-315.
Thus, in comparison to tacrolimus coadministration, MPA plasma levels may be reduced with coadministration of cyclosporine. Due to the variability in patient plasma MPA levels, monitoring MPA levels may help to optimize outcomes in patients with high risks of organ rejection after transplantation.
LREFVan Gelder T, Meur YL, Shaw LM, et al. Therapeutic drug monitoring of mycophenolate mofetil in transplantation. Ther Drug Monit 2006;28(2):145-154.
,
LREFMeiser BM, Pfeiffer M, Schmidt D, et al. Combination therapy with tacrolimus and mycophenolate mofetil following cardiac transplantation:importance of mycophenolic acid therapeutic drug monitoring. J Heart Lung Transplant 1999;18(2):143-149.

", "Language": "en" }, { "Name": "Reagents", "Value": "

Reagents - working solutions

R1

IMPDH‑II in buffer: 15.7 U/L; IMP: 4.8 mmol/L; stabilizer; preservative

R2

NAD: 10 mmol/L in buffer; stabilizer; preservative.

R1 is in position B and R2 is in position C.

", "Language": "en" }, { "Name": "PrecautionsWarnings", "Value": "

Precautions and warnings

For in vitro diagnostic use for health care professionals. Exercise the normal precautions required for handling all laboratory reagents.

Infectious or microbial waste:
Warning: handle waste as potentially biohazardous material. Dispose of waste according to accepted laboratory instructions and procedures.

Environmental hazards:
Apply all relevant local disposal regulations to determine the safe disposal.

Safety data sheet available for professional user on request.

This kit contains components classified as follows in accordance with the Regulation (EC) No. 1272/2008:

Danger

H350

May cause cancer.

Prevention:

P201

Obtain special instructions before use.

P202

Do not handle until all safety precautions have been read and understood.

P280

Wear protective gloves/ protective clothing/ eye protection/ face protection/ hearing protection.

Response:

P308 + P313

IF exposed or concerned: Get medical advice/attention.

Storage:

P405

Store locked up.

Disposal:

P501

Dispose of contents/container to an approved waste disposal plant.

EUH 208

Contains Sodium Hydroxymethylglycinate. May produce an allergic reaction.

Product safety labeling follows EU GHS guidance.

Contact phone: all countries: +49-621-7590

", "Language": "en" }, { "Name": "Caution", "Value": "", "Language": "en" }, { "Name": "QualityControl", "Value": "

Quality control

For quality control, use control materials as listed in the “Order information” section. In addition, other suitable control material can be used.

The control intervals and limits should be adapted to each laboratory’s individual requirements. It is recommended to perform quality control always after lot calibration and subsequently at least every 12 weeks.

Values obtained should fall within the defined limits. Each laboratory should establish corrective measures to be taken if values fall outside the defined limits.

Follow the applicable government regulations and local guidelines for quality control.

", "Language": "en" }, { "Name": "SpecimenPreparation", "Value": "

Specimen collection and preparation

For specimen collection and preparation only use suitable tubes or collection containers.

Only the specimens listed below were tested and found acceptable.
Serum: Collect serum using standard sampling tubes.
Plasma: K2‑ and K3‑EDTA plasma.

The sample types listed were tested with a selection of sample collection tubes that were commercially available at the time of testing, i.e. not all available tubes of all manufacturers were tested. Sample collection systems from various manufacturers may contain differing materials which could affect the test results in some cases. When processing samples in primary tubes (sample collection systems), follow the instructions of the tube manufacturer.

Centrifuge samples containing precipitates before performing the assay.

See the limitations and interferences section for details about possible sample interferences.

Sample stability claims were established by experimental data by the manufacturer or based on reference literature and only for the temperatures/time frames as stated in the method sheet. It is the responsibility of the individual laboratory to use all available references and/or its own studies to determine specific stability criteria for its laboratory.

Specimens should be tested within 8 hours of collection if kept at room temperature. If specimens must be stored for later testing, they should be kept at 2 to 8 °C for up to 96 hours or at -20 °C or below for up to 11 months.

LREFShaw LM, Holt DW, Oellerich M, et al. Current issues in therapeutic drug monitoring of mycophenolic acid: Report of a roundtable discussion. Ther Drug Monit 2001;23(4):305-315.
,
LREFShipkova M, Armstrong VM, Schneider T, et al. Stability of mycophenolic acid glucuronide in human plasma. Clin Chem 1999;45(1):127-129.
Specimens should not be repeatedly frozen and thawed (do not exceed 5 freeze/thaw cycles).

Invert thawed specimens several times prior to testing.

", "Language": "en" } ] } } ] }

MPA

Mycophenolic Acid - Total Mycophenolic Acid Application

IVD For in vitro diagnostic use.
MPA

Overview

Detailed Specifications

Ordering Information

Compatible Instruments

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    ...

    Technical Documents

    Access Material Data Sheets, Certificates of Analysis, and other product documentation.

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