Comparing Mycophenolate Mofetil Regimens for de Novo Renal Transplant Recipients: The Fixed-Dose Concentration-Controlled Trial

Gelder, Teun van; Silva, Helio Tedesco; Fijter, Johan W. de; Budde, Klemens; Kuypers, Dirk; Tydén, G; Lõhmus, Aleksander; Sommerer, Claudia; Hartmann, Anders; Meur, Yann Le; Oellerich, Michael; Holt, David W.; Tönshoff, Burkhard; Keown, Paul; Campbell, Scott; Mamelok, Richard D.

doi:10.1097/tp.0b013e318186f98a

Cited by 251 publications

(238 citation statements)

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“…Drug monitoring was never correlated with a lower incidence of therapy failure with mycophenolate mofetil, which was confirmed in a recent study. 16 However, so far, MPA monitoring was performed by measuring plasma concentrations, and pharmacogenetic factors such as polymorphisms were not considered. Thus, there is growing interest in the impact of genetic polymorphisms of drug-metabolizing enzymes and transporters on drug efficacy.…”

Section: Discussionmentioning

confidence: 99%

An inosine 5′-monophosphate dehydrogenase 2 single-nucleotide polymorphism impairs the effect of mycophenolic acid

et al. 2009

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Mycophenolic acid (MPA) is a selective inhibitor of inosine 5 0 -monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme of de novo synthesis of guanine nucleotides. The isoenzyme IMPDH2 predominates in activated lymphocytes, and its inhibition by MPA is part of standard immunosuppressive regimens. Yet, there are significant unexplained differences in efficacy and tolerability among patients. The objective of this study was to analyze whether frequent variants in the IMPDH2 gene lead to changes in IMPDH activity and to differences in responsiveness to MPA therapy. All 14 exons and intron-exon boundary regions of IMPDH2 were sequenced from genomic DNA probes from 100 healthy individuals. Two novel exonic single-nucleotide polymorphisms were identified in 1% and one intronic polymorphism (rs11706052) in 19% of the study population. Lymphocyte IMPDH activity and proliferation under three MPA concentrations (2.5, 10 and 25 mmol l -1 ) were compared in rs11706052 carriers and wild-type individuals. The presence of rs11706052 polymorphism reduced the antiproliferative effect of MPA on lymphocytes by approximately 50% compared with the IMPDH2 wild-type form at therapeutic relevant concentrations of 10 mmol l -1 and 25 mmol l -1 . We conclude that a poorer response to MPA therapy can be explained in some individuals by the presence of the rs11706052 polymorphism.

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Section: Discussionmentioning

confidence: 99%

An inosine 5′-monophosphate dehydrogenase 2 single-nucleotide polymorphism impairs the effect of mycophenolic acid

et al. 2009

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“…Similarly, mean MPA-AUC of CsAtreated patients on day 10 was 34.4 mg/h per L in the FixedDose Concentration-Controlled (FDCC) Study (13). The authors concluded that higher MPA dosages seemed to be necessary to reach early target AUC in CsA-treated populations (13).…”

Section: Discussionmentioning

confidence: 99%

“…Median MPA-AUC was only 33.7 mg/h per L on day 14 in the Apomygre study, and levels Ͼ40 mg/h per L were not achieved until month 1 using a concentration-controlled approach (12). Similarly, mean MPA-AUC of CsAtreated patients on day 10 was 34.4 mg/h per L in the FixedDose Concentration-Controlled (FDCC) Study (13). The authors concluded that higher MPA dosages seemed to be necessary to reach early target AUC in CsA-treated populations (13).…”

Section: Discussionmentioning

confidence: 99%

“…Whereas the majority of tacrolimus-treated patients achieve adequate MPA exposure early after transplantation (13,14), studies have demonstrated that approximately 50% of patients who are treated with CsA and standard MPA dosages are underexposed (4,7,12,13). Larger initial MMF dosages (up to 4 g/d) have been suggested early after transplantation for achievement of sufficient MPA exposure in combination with CsA (13,15,16).…”

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confidence: 99%

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Pharmacokinetics and Pharmacodynamics of Intensified versus Standard Dosing of Mycophenolate Sodium in Renal Transplant Patients

Glander¹,

Sommerer²,

Arns³

et al. 2010

Clinical Journal of the American Society of Nephrology

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Background and objectives: Adequate early mycophenolic acid (MPA) exposure is an important determinant for effective rejection prophylaxis. This pharmacokinetic study investigated whether an intensified dosing regimen of enteric-coated mycophenolate sodium (EC-MPS) could achieve higher mycophenolic acid (MPA) exposure early after transplantation versus a standard dosing regimen.Design, setting, participants, & measurements: De novo kidney transplant recipients (n ‫؍‬ 75) who were treated with basiliximab induction and cyclosporine were randomly assigned to receive EC-MPS as either standard dosing (1440 mg/d; n ‫؍‬ 37) or intensified dosing (days 0 through 14: 2880 mg/d; days 15 through 42: 2160 mg/d; followed by 1440 mg/d; n ‫؍‬ 38). Full 12-hour pharmacokinetic and pharmacodynamic profiles were taken at six time points during the first 3 months. Exploratory analysis of inosine monophosphate dehydrogenase (IMPDH) activity was also performed for better understanding of the pharmacokinetic-pharmacodynamic relationship between MPA exposure and IMPDH activity in the early posttransplantation period. Preliminary efficacy parameters, safety, and tolerability were assessed.Results: Exposure to MPA was significantly higher on days 3 and 10 after transplantation in the intensified versus standard EC-MPS group, with 52.9 versus 22.2% (P < 0.05) of patients reaching MPA exposure >40 mg/h per L in the first week. The intensified regimen resulted in significantly lower IMPDH activity on day 3 after transplantation, and the overall safety was comparable for both groups.Conclusions: These pharmacokinetic and safety data support further research on the hypothesis that early adequate MPA exposure could improve clinical outcome.

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“…The aim of the present report was to evaluate whether taking the CYP3A4*22 allelic status into account affects the predictive value of the algorithm developed by Passey et al [3].The patients included in the present analysis were 185 de novo kidney transplant recipients treated with a tacrolimus-based regimen who participated in a trial comparing fixed-dose (FD) with concentration-controlled (CC) mycophenolate mofetil (MMF) treatment [4]. All patients had been previously genotyped for CYP3A4*22 and CYP3A5*3 alleles [1].…”

Section: Boxmentioning

confidence: 99%

The CYP3A422* allele affects the predictive value of a pharmacogenetic algorithm predicting tacrolimus predose concentrations

Elens

Hesselink

Schaik

et al. 2013

Brit J Clinical Pharma

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Comparing Mycophenolate Mofetil Regimens for de Novo Renal Transplant Recipients: The Fixed-Dose Concentration-Controlled Trial

Cited by 251 publications

References 21 publications

An inosine 5′-monophosphate dehydrogenase 2 single-nucleotide polymorphism impairs the effect of mycophenolic acid

An inosine 5′-monophosphate dehydrogenase 2 single-nucleotide polymorphism impairs the effect of mycophenolic acid

Pharmacokinetics and Pharmacodynamics of Intensified versus Standard Dosing of Mycophenolate Sodium in Renal Transplant Patients

The CYP3A422* allele affects the predictive value of a pharmacogenetic algorithm predicting tacrolimus predose concentrations

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Comparing Mycophenolate Mofetil Regimens for de Novo Renal Transplant Recipients: The Fixed-Dose Concentration-Controlled Trial

Cited by 251 publications

References 21 publications

An inosine 5′-monophosphate dehydrogenase 2 single-nucleotide polymorphism impairs the effect of mycophenolic acid

An inosine 5′-monophosphate dehydrogenase 2 single-nucleotide polymorphism impairs the effect of mycophenolic acid

Pharmacokinetics and Pharmacodynamics of Intensified versus Standard Dosing of Mycophenolate Sodium in Renal Transplant Patients

The CYP3A4*22 allele affects the predictive value of a pharmacogenetic algorithm predicting tacrolimus predose concentrations

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The CYP3A422* allele affects the predictive value of a pharmacogenetic algorithm predicting tacrolimus predose concentrations