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


CONCLUSIONS
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.
Department of Nephrology, Charité University Hospital Berlin, Berlin, Germany.|Institute of Pharmacy, Department of Biology, Chemistry, Pharmacy, Freie Universitaet Berlin, Berlin, Germany.
Olesja
O
Rissling
Department of Nephrology, Charité University Hospital Berlin, Berlin, Germany.
Petra
P
Glander
Department of Nephrology, Charité University Hospital Berlin, Berlin, Germany.
Pia
P
Hambach
Department of Nephrology, Charité University Hospital Berlin, Berlin, Germany.
Marco
M
Mai
Department of Nephrology, Charité University Hospital Berlin, Berlin, Germany.
Susanne
S
Brakemeier
Department of Nephrology, Charité University Hospital Berlin, Berlin, Germany.
Daniela
D
Klonower
Department of Nephrology, Charité University Hospital Berlin, Berlin, Germany.
Fabian
F
Halleck
Department of Nephrology, Charité University Hospital Berlin, Berlin, Germany.
Eugenia
E
Singer
Department of Nephrology, Charité University Hospital Berlin, Berlin, Germany.
Eva-Vanessa
EV
Schrezenmeier
Department of Nephrology, Charité University Hospital Berlin, Berlin, Germany.
Michael
M
Dürr
Department of Nephrology, Charité University Hospital Berlin, Berlin, Germany.
Hans-Hellmut
HH
Neumayer
Department of Nephrology, Charité University Hospital Berlin, Berlin, Germany.
Klemens
K
Budde
D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D000897:Anti-Ulcer Agents / Q000008:administration & dosage / Q000494:pharmacology; D018592:Cross-Over Studies; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D005260:Female; D020719:Glucuronides / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D007168:IMP Dehydrogenase / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000276:immunology / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000276:immunology / Q000493:pharmacokinetics*; D000077402:Pantoprazole; D013608:Tablets, Enteric-Coated / Q000493:pharmacokinetics; D013810:Therapeutic Equivalency
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000897:Anti-Ulcer Agents; D004791:Enzyme Inhibitors; D020719:Glucuronides; D007166:Immunosuppressive Agents; D013608:Tablets, Enteric-Coated; C113145:mycophenolic acid glucuronide; D000077402:Pantoprazole; D007168:IMP Dehydrogenase; C488211:IMPDH1 protein, human; D009173:Mycophenolic Acid
drug-drug interaction; immunosuppression; mycophenolic acid; pantoprazole; pharmacodynamics; pharmacokinetics