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

Abstract

AIMSMycophenolic 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. METHODSIn this single-centre, open, randomized, four-sequence, four-treatment crossover study, the influence of PAN 40 mg on MPA pharmacokinetics such as (dose-adjusted) AUC 0-12 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 CONCLUSIONPantoprazole influences EC-MPS and MMF pharmacokinetics but as it had no impact on MPA pharmacodynamics, the immunosuppressive effect of the drug was not impaired. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Pantoprazole is a frequently prescribed proton pump inhibitor (PPI) in renal transplant patients as gastrointestinal side effects, such as heartburn, are common under immunosuppressive therapy with mycophenolate.• PPIs influence the bioavailability of drugs by raising gastric pH, which may lead to different dissolution rates or changes in the solubility of drugs. WHAT THIS STUDY ADDS• This crossover study analysed the effect of pantoprazole on MMF and EC-MPS pharmacokinetics in renal transplant patients under maintenance immunosuppressive therapy.• For pantoprazole intake, bioequivalence was not established for either MMF or EC-MPS.• Further analysis showed no impact of pantoprazole on MPAG pharmacokinetics or MPA pharmacodynamics.

Different Routes of Proton Pumps Inhibitors Co-Administration have Significant Impact on Mycophenolate Acid (MPA) Serum Levels in Heart Transplant Recipients

“…Moreover, our study results were contrary to common clinical beliefs and previous reports regarding to MPA serum concentration with PPIs therapy [12]. We focused on the AUC curve, which is more accurate for evaluation of MPA serum concentration as previous reported in studies of kidney transplantation patients [13].…”

“…The results of nonsignificant association between oral intake of PPIs and MPA serum plasma concentration have been previously presented [13]. The most commonly administered dose of pantoprazole (40 mg/day) was chosen for the study.…”

Mycophenolic Acid and Its Pharmacokinetic Drug‐Drug Interactions in Humans: Review of the Evidence and Clinical Implications

“…The overall findings indicate significant PK DDIs between MMF and lansoprazole, omeprazole, or pantoprazole (Table ) . Coadministration of any of those PPIs with MMF results in impaired bioavailability of MPA in both healthy individuals and transplant recipients .…”

The Effect of Proton Pump Inhibitor Use on Renal Function in Kidney Transplanted Patients

“…Decreased MPA exposure can increase rejection rates [13][14][15][16]. However, in a recent pharmacokinetic blinded cross-over study [49], this mentioned interaction was not found. In line with this and with previously published observational studies, rejection rates in our cohort were comparable between groups [22,24,25].…”