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Oremus M, Zeidler J, Ensom MHH, et al. Utility of Monitoring Mycophenolic Acid in Solid Organ Transplant Patients. Rockville (MD): Agency for Healthcare Research and Quality (US); 2008 Feb. (Evidence Reports/Technology Assessments, No. 164.)

Cover of Utility of Monitoring Mycophenolic Acid in Solid Organ Transplant Patients

Utility of Monitoring Mycophenolic Acid in Solid Organ Transplant Patients.

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Executive Summary

Introduction

Mycophenolic acid (MPA) is an immunosuppressant drug used to prevent rejection of solid organ transplants. The drug is marketed as the ester prodrug mycophenolate mofetil (MMF)(CellCept®) for kidney, liver, and heart transplants or enteric-coated mycophenolate sodium (Myfortic®) (ECMPS) for kidney transplants.1

Therapeutic drug monitoring of MPA has the objective of improving control over acute rejection. It is based on observed associations between pharmacokinetic (PK) parameters such as total MPA area under the concentration-time curve (AUC0 – 12) and acute rejection in adult and pediatric patients.2,3

This evidence report was commissioned to address the following key questions:

1.

What is the evidence that monitoring mycophenolic acid in patients who receive a solid organ transplant results in a lower incidence of transplant rejections and adverse events compared to patients who are not monitored?

2.

Does the incidence differ by any of the following?

a)

MPA dose and dose frequency;

b)

Type of MPA (mycophenolate mofetil [CellCept®], enteric-coated mycophenolate sodium [Myfortic®]).

3.
a)

Does the incidence differ by any of the following?

ia)

Total versus free MPA

ib)

Albumin versus MPA

iia)

MPAG, AcMPAG versus MPA

iib)

Genetic basis of differences in MPA pharmacokinetic parameters

iii)

Assay method (HPLC, EMIT, HPLC-MS, other)

b)

Does the incidence differ by analytical method of MPA monitoring?

i.

Full AUC

ii.

Limited sampling strategies

a.

Predose concentrations

b.

2h post dose concentrations

c.

Other

4.

Does the evidence for monitoring MPA differ by any of the following?

a)

Age

b)

Gender

c)

Ethnicity

d)

Concomitant use of calcineurin inhibitors (e.g., tacrolimus, cyclosporine)

e)

Concomitant use of other medications

f)

Comorbidity

5.

What is the short- and long-term cost-effectiveness of avoiding acute rejection due to MPA monitoring?

Methods

The following electronic databases were searched up until October 22, 2007:

1.

MEDLINE® (1966-);

2.

BIOSIS® Previews (1976-);

3.

EMBASE® (1980-);

4.

Cochrane Database of Systematic Reviews® (1995-);

5.

Cochrane Central Register of Controlled Trials® (1995-).

We examined the reference lists of several recently published review articles36 and consulted with the technical expert panel to identify additional published studies.

Inclusion/exclusion criteria. We included randomized controlled trials, observational studies with comparison groups, or case series, published in the English language. We included studies of pediatric and adult patients who received allograft solid organ transplants, provided that any form of MPA was measured in serum or plasma, using any method of measurement (e.g., AUC).

Data Collection and Reliability of Study Selection. A team of trained raters applied the inclusion and exclusion criteria to the citations identified in the literature search. Each citation was screened by two independent raters and had to pass two levels of screening (title and abstract, full text) prior to data abstraction.

Quality Assessment of Included Studies. The methodological quality of included studies was assessed independently by two raters using ‘core’ criteria enumerated in the draft Evidence-based Practice Centre Methods Manual (under preparation by the AHRQ).

Results

The literature search yielded 11,642 citations, from which 495 (4 percent) proceeded to full text screening. Of these 495 citations, 89 (18 percent) were included in the report and abstracted.

What is the Evidence That Monitoring Mycophenolic Acid in Patients who Receive a Solid Organ Transplant Results in a Lower Incidence of Transplant Rejections and Adverse Events Compared to Patients who are not Monitored?

Only three studies addressed this question (four reports).710 Patients in the concentration-controlled group had fewer rejections than patients in the fixed-dose group in two studies (no p-value reported in one study; p=0.01 in the other study). In the third study, there were more rejections in the concentration-controlled group (p>0.05).

Does the Incidence Differ by MPA Dose and Dose Frequency?

Only one study compared rejection outcomes for subjects with planned dose adjustments based on different target MPA plasma concentrations.11,12 In this RCT of kidney transplant recipients, the incidence of biopsy-proven acute rejection was inversely associated with increasing pre-defined MPA AUC concentration-control levels (p=0.043).

Does the Incidence Differ by Type of MPA (Mycophenolate Mofetil, Enteric-coated Mycophenolate Sodium)?

There was no evidence in the included studies to answer this question.

Does the Incidence Differ by Total versus free MPA, Albumin, Genetic Differences, Metabolites?

Free versus total MPA. The incidence of rejection or adverse events was found to differ significantly between free and total MPA in only one13 of nine studies1321 that examined both forms of MPA.

Albumin. Studies generally found that impaired kidney function and hypoalbuminemia were associated with increased concentrations or AUCs of free MPA, but not total MPA.

Pharmacogenetic. Seven days after transplantation, renal allograft recipients (n=9) without the C-24T Single Nucleotide Polymorphisms (SNP) of the multidrug resistance-associated protein 2 (MRP2), but with mild liver dysfunction, had lower MPA exposure compared to MRP2 C-24T non-carriers (n=45) without liver dysfunction. MPA pharmacokinetic (PK) parameters were found to vary with the time of the day (daytime AUC > nighttime AUC). No direct associations between genotype, MPA PK parameters, and outcomes were found.

Metabolites. Two15,16 of seven studies15,16,20,2225 found associations between MPA metabolite concentrations and adverse events. Higher median acyl glucuronide metabolite of mycophenolic acid (AcMPAG) (p=0.03), mycophenolic acid glucuronide (MPAG) C0 concentrations (p=0.02), and AcMPAG/MPA ratios (p=0.004), but not higher MPA C0 concentrations (p>0.05) were found in patients at times when they experienced anemia versus times when with no anemia.15 The authors also found lower median MPAG C0 concentrations at times of a leucopenia episode versus times of no episode (p=0.04). In the second study16, a correlation was found between the amount of fecal fat loss and MPAG concentrations (r=0.9955, p<0.001), as well as AcMPAG concentrations (r=0.90, p=0.015) in five renal allograft recipients with persistent afebrile diarrhea.

Does the Incidence Differ by Assay Method?

Only two case series26,27 involved direct comparisons of different assay methods (enzyme-multiplied immunoassay technique (EMIT) versus high-performance liquid chromatography (HPLC)). Both reports included children with transplanted kidneys from the same research project. EMIT and HPLC were equally able to discriminate between patients with acute rejections during the first 70 days post-transplant. Decision concentrations, below which the risk of acute rejection is increased, were higher with EMIT than with HPLC. None of the PK parameters, regardless of assay method, were associated with the incidence of adverse events.

Does the Incidence Differ by Analytical Method of MPA Monitoring?

Ten studies (11 reports)11,12,17,2633 showed AUC0–12 to be related to rejection, while 4 studies 3437 showed no relation. There were 17 positive studies (18 reports)7,8,12,26,27,30,33,3848 linking (predose, C0, Cmin, or C12) concentration to rejection and 25 negative studies.11,15,17,19,24,25,28,36,37,42,45,4962 Only one study 57found C2 to be a significant predictor of rejection while one other study 54 did not. Eleven studies 10,17,19,26,43,49,54,57,59,63,64 found other limited sampling strategies (i.e., involving C0, C20min, C30min, C40min, C1, C75min, C2, C3, C4, C6, AUC0–9) be related to rejection whereas 9 studies 11,13,17,26,36,51,52,54,65 found no relationship. Four studies31,33,36,46 showed that AUC0–12 is associated with adverse effects, while 11 studies (12 reports)11,12,17,26,29,32,3537,52,66,67 showed no association. There were 18 studies14,16,33,36,3941,45,48,56,61,6874 demonstrating associations between predose concentration (predose, C0, Cmin, or C12) and adverse effects, and 24 studies (25 reports)11,12,14,15,17,18,20,22,25,26,36,37,42,47,49,52,54,57,62,64,66,67,72,75,76 demonstrating no associations. No studies found C2 to be a significant predictor of adverse effects and two54,57 found no association. Five studies33,59,6567 found other limited sampling strategies (C0, C30min, C40min, C1, C3, C6) to be associated with adverse effects while 17 studies10,11,13,17,20,21,26,36,49,52,54,57,64,66,7577 showed the opposite.

Does the Evidence for Monitoring MPA Differ by Age, Gender, Ethnicity, Concomitant use of Calcineurin Inhibitors or Other Medications, or Comorbidity?

Some of the six factors of this question appear to influence MPA PK parameters. None of the included studies investigated whether PK parameter concentrations, stratified by each factor, were associated with outcomes such as rejection or adverse events. Regarding age, the evidence was equivocal. In pediatric populations, younger children were found to require a higher MMF dose to achieve a specified MPA concentration. When given the same dose of MMF, the MPA AUC has been reported to be lower in the elderly compared to younger adults. Regarding gender, the evidence appears to indicate that PK parameters are higher for females versus males. Race and ethnicity do not appear to influence MPA PK parameters. Calcineurin inhibitors and sirolimus are co-administered frequently with MMF and the bulk of the evidence found that exposure to MPA is higher in patients receiving tacrolimus or sirolimus compared to cyclosporine, with lower doses of MMF required in combination with tacrolimus to achieve adequate MPA exposure. MPA PK parameters were generally higher in persons with renal insufficiency, although one study20 found lowered MPA AUC in the early post-transplant period.

What is the Short and Long-Term Cost-Effectiveness of Avoiding Acute Rejection due to MPA Monitoring?

None of the abstracted studies contained any data on the cost-effectiveness of MPA monitoring.

Quality Assessment of Abstracted Studies

Twelve of the 89 abstracted studies were RCTs1012,25,28,29,34,50,51,65,68,78 and the remainder were observational studies (primarily case series). The quality of the RCTs was fair to good, although reporting of some essential features of trial design was lacking (e.g., method of randomization, blinding).

Compared to the RCTs, the 77 observational studies suffered from numerous reporting problems. Virtually all of the studies lacked reports of blinding among subjects (n=73), persons measuring MPA (n=74), and outcomes assessors (n=75). Differential losses to followup were not reported in 61 studies. The authors of only 29 studies made an attempt to control for confounding. Some aspects of reporting were good, though, as the authors of most of the observational studies described the methods used to measure MPA (n=68) and clearly defined their outcomes (n=69).

Discussion

What is the Evidence That Monitoring Mycophenolic Acid in Patients who Receive a Solid Organ Transplant Results in a Lower Incidence of Transplant Rejections and Adverse Events Compared to Patients who are not Monitored?

Three studies (four reports)710 directly addressed this question, although the first study was not designed to compare monitoring versus no monitoring and the second study9 found no evidence to suggest that monitored patients had a lower incidence of transplant rejections relative to non-monitored patients. The third study,10 the first published RCT to compare monitoring versus no monitoring of MPA in any patient group, found a lower incidence of treatment failures in the monitored group. However, the RCT is limited to adult kidney transplant patients, so the efficacy of monitoring in other patient populations is still unknown. Likewise, the clinical applicability of the trial's limited AUC sampling strategy, or the applicability of the 40 mg*h/L MPA target dose, to these other populations is also unknown.

Does the Incidence Differ by MPA Dose and Dose Frequency?

The evidence to support an association between MMF dosage and rejection is inconclusive. Most studies were not designed to directly assess whether there was an association between MMF dosage and rejection or adverse events. Solid clinical recommendations can only be made after further research is conducted, preferably using RCTs to compare different fixed doses and different targets for concentration control.

Does the Incidence Differ by Type of MPA?

None of the included studies directly compared ECMPS with MMF, so this question could not be answered.

Does the Incidence Differ by Total Versus Free MPA, Albumin, Genetic Differences, Metabolites?

None of the included studies confirmed the hypothesis that measurements of free MPA correlate better with outcomes than total MPA, although free (not total) MPA was found to be associated with infections and haematological adverse events in three studies.13,14,17

One pharmacogenetic study79 showed that carriers of the two multidrug resistance protein (MRP2) single nucleotide polymorphisms (SNP) were protected from reduced MPA exposure in mild liver dysfunction. A second genetic study found associations between MPA and genes, genes and diarrhea, and MPA and rejection. The clinical relevance of both studies to MPA monitoring is unclear.

The studies regarding metabolites yielded few positive results.15,16 Larger, randomized trials are necessary to establish the utility of monitoring MPA and its metabolites.

Does the Incidence Differ by Assay Method?

In two studies,26,27 HPLC and EMIT performed similarly well in the assessment of acute rejection risk in pediatric kidney transplant patients. EMIT cut off values were higher than those derived from HPLC measurements. The study populations were pediatric patients, and it remains to be seen whether diagnostic sensitivities and specificities between HPLC and EMIT would differ in other populations.

Does the Incidence Differ by Analytical Method of MPA Monitoring?

There was no evidence to directly answer this key question.

Does the Evidence Differ by Age, Gender, Ethnicity, Concomitant Use of Calcineurin Inhibitors or Other Medications, or Comorbidity?

The evidence from the literature failed to directly address the key question. Of the studies that were included in the report, the focus was on adults and kidney transplant recipients. Few studies involved children or other solid organ transplants. Also, study findings were difficult to compare because measures of MPA in the serum or plasma sometimes exhibit large intra- and inter-patient variability over time post transplant.

What is the Short- and Long-Term Cost-Effectiveness of Avoiding Acute Rejection Due to MPA Monitoring?

The published literature contains no data on the cost-effectiveness of monitoring versus no monitoring in solid organ transplants. Therefore, it is not possible to answer this key question.

Limitations of this Evidence Report

Only English-language, published studies were included in this report, thereby introducing the possibility of publication bias. Virtually all of the included studies involved MMF rather than ECMPS. Therefore, the conclusions may not be applicable to the enteric-coated formulation.

Conclusions

The state of knowledge about therapeutic drug monitoring of MPA in solid organ transplants is still in its infancy. This is especially so for organs other than the kidney because the overwhelming majority of published studies involve kidney transplant patients. Overall, the published evidence on MPA monitoring is inconclusive; there is almost no direct evidence to suggest that monitoring would reduce the incidence of rejection or adverse events in any solid organ transplant. Each of the key questions in this report would be more adequately addressed using RCTs.

Clinical recommendations. There is almost no direct evidence to suggest that monitoring is more or less beneficial than not monitoring. Until there is more evidence on the utility of routine MPA monitoring in solid organ transplant recipients, patients, clinicians, and other stakeholders (e.g., public and private insurers) will have to decide on a case by case basis whether the possible but uncertain benefits are worth the extra time and expense of monitoring.

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