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No relevant pharmacokinetic interaction between pantoprazole and mycophenolate in renal transplant patients: a randomized crossover study.

Abstract：

AIMS:Mycophenolic acid (MPA) suppresses lymphocyte proliferation through inosine monophosphate dehydrogenase (IMPDH) inhibition. Two formulations have been approved: mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS). Pantoprazole (PAN) inhibits gastric acid secretion, which may alter MPA exposure. Data from healthy volunteers suggest a significant drug-drug interaction (DDA) between pantoprazole and MPA. In transplant patients, a decreased MPA area under the concentration-time curve (AUC) may lead to higher IMPDH activity, which may lead to higher acute rejection risk. Therefore this DDA was evaluated in renal transplant patients under maintenance immunosuppressive therapy. METHODS:In this single-centre, open, randomized, four-sequence, four-treatment crossover study, the influence of PAN 40 mg on MPA pharmacokinetics such as (dose-adjusted) AUC0-12 h (dAUC) was analysed in 20 renal transplant patients (>6 months post-transplantation) receiving MMF (1-2 g day(-1) ) and EC-MPS in combination with ciclosporin. The major metabolite MPA glucuronide (MPAG) and the IMPDH activity were also examined. RESULTS:MMF + PAN intake led to a lowest mean dAUC for MPA of 41.46 ng h ml(-1) mg(-1) [95% confidence interval (CI) 32.38, 50.54], while MPA exposure was highest for EC-MPS + PAN [dAUC: 46.30 ng h ml(-1) mg(-1) (95% CI 37.11, 55.49)]. Differences in dAUC and dose-adjusted maximum concentration (dCmax) were not significant. Only for MMF [dAUC: 41.46 ng h ml(-1) mg(-1) (95% CI 32.38, 50.54)] and EC-MPS [dAUC: 43.39 ng h ml(-1) mg(-1) (95% CI 33.44, 53.34)] bioequivalence was established for dAUC [geometric mean ratio: 101.25% (90% CI 84.60, 121.17)]. Simultaneous EC-MPS + PAN intake led to an earlier time to Cmax (tmax) [median: 2.0 h (min-max: 0.5-10.0)] than EC-MPS intake alone [3 h (1.5-12.0); P = 0.037]. Tmax was not affected for MMF [1.0 h (0.5-5.0)] ± pantoprazole [1.0 h (0.5-6.0), P = 0.928). No impact on MPAG pharmacokinetics or IMPDH activity was found. CONCLUSION:Pantoprazole influences EC-MPS and MMF pharmacokinetics but as it had no impact on MPA pharmacodynamics, the immunosuppressive effect of the drug was not impaired.

journal_name

Br J Clin Pharmacol

journal_title

British journal of clinical pharmacology

authors

Rissling O,Glander P,Hambach P,Mai M,Brakemeier S,Klonower D,Halleck F,Singer E,Schrezenmeier EV,Dürr M,Neumayer HH,Budde K

doi

10.1111/bcp.12664

subject

Has Abstract

pub_date

2015-11-01 00:00:00

pages

1086-96

issue

eissn

0306-5251

issn

1365-2125

journal_volume

pub_type

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No relevant pharmacokinetic interaction between pantoprazole and mycophenolate in renal transplant patients: a randomized crossover study.