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

ABSTRACT: 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.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.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.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.

SUBMITTER: Rissling O

PROVIDER: S-EPMC4631181 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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

Rissling Olesja O Glander Petra P Hambach Pia P Mai Marco M Brakemeier Susanne S Klonower Daniela D Halleck Fabian F Singer Eugenia E Schrezenmeier Eva-Vanessa EV Dürr Michael M Neumayer Hans-Hellmut HH Budde Klemens K

British journal of clinical pharmacology 20150714 5

<h4>Aims</h4>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 co ...[more]

PMID: 25913040

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Project description:PurposeThe combined administration of bazedoxifene, a tissue-selective estrogen receptor modulator, and cholecalciferol can be a promising therapeutic option for postmenopausal osteoporosis patients. This study aimed to examine the pharmacokinetic interactions between these two drugs and the tolerability of their combined administration in healthy male subjects.Patients and methodsThirty male volunteers were randomly assigned to one of the six sequences comprised of three treatments: bazedoxifene 20 mg monotherapy, cholecalciferol 1600 IU monotherapy, and combined bazedoxifene and cholecalciferol therapy. For each treatment, a single dose of the investigational drug(s) was administered orally, and serial blood samples were collected to measure the plasma concentrations of bazedoxifene and cholecalciferol. Pharmacokinetic parameters were calculated using the non-compartmental method. The point estimate and 90% confidence interval (CI) of the geometric mean ratio (GMR) were obtained to compare the exposures of combined therapy and monotherapy. The pharmacokinetic parameters compared were the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve from time zero to the last quantifiable concentration (AUClast). The safety and tolerability of the combined therapy were assessed in terms of the frequency and severity of adverse events (AEs).ResultsFor bazedoxifene, the GMR (90% CI) of the combined therapy to monotherapy was 1.044 (0.9263-1.1765) for Cmax and 1.1329 (1.0232-1.2544) for AUClast. For baseline-adjusted cholecalciferol, the GMR (90% CI) of the combined therapy to monotherapy was 0.8543 (0.8005-0.9117) for Cmax and 0.8056 (0.7445-0.8717) for AUClast. The frequency of AEs observed was not significantly different between the combined therapy and monotherapy, and their severity was mild in all cases.ConclusionA mild degree of pharmacokinetic interaction was observed when bazedoxifene and cholecalciferol were administered concomitantly to healthy male volunteers. This combined therapy was well tolerated at the dose levels used in the present study.

Project description:Background: Voriconazole an antifungal drug, has a potential for drug-drug interactions (DDIs) with administered drugs. Clarithromycin is a Cytochromes P450 CYP (3A4 and 2C19) enzyme inhibitor, and voriconazole is a substrate and inhibitor of these two enzymes. Being a substrate of the same enzyme for metabolism and transport, the chemical nature and pKa of both interacting drugs make these drugs better candidates for potential pharmacokinetic drug-drug interactions (PK-DDIs). This study aimed to evaluate the effect of clarithromycin on the pharmacokinetic profile of voriconazole in healthy volunteers. Methods: A single oral dose, open-label, randomized, crossover study was designed for assessing PK-DDI in healthy volunteers, consisting of 2 weeks washout period. Voriconazole, either alone (2 mg × 200 mg, tablet, P/O) or along with clarithromycin (voriconazole 2 mg × 200 mg, tablet + clarithromycin 500 mg, tablet, P/O), was administered to enrolled volunteers in two sequences. The blood samples (approximately 3 cc) were collected from volunteers for up to 24 h. Plasma concentrations of voriconazole were analyzed by an isocratic, reversed-phase high-performance-liquid chromatography ultraviolet-visible detector (RP HPLC UV-Vis) and a non-compartmental method. Results: In the present study, when voriconazole was administered with clarithromycin versus administered alone, a significant increase in peak plasma concentration (Cmax) of voriconazole by 52% (geometric mean ratio GMR: 1.52; 90% CI 1.04, 1.55; p = 0.000) was observed. Similarly, the area under the curve from time zero to infinity (AUC0-∞) and the area under the concentration-time curve from time zero to time-t (AUC0-t) of voriconazole also significantly increased by 21% (GMR: 1.14; 90% CI 9.09, 10.02; p = 0.013), and 16% (GMR: 1.15; 90% CI 8.08, 10.02; p = 0.007), respectively. In addition, the results also showed a reduction in the apparent volume of distribution (Vd) by 23% (GMR: 0.76; 90% CI 5.00, 6.20; p = 0.051), and apparent clearance (CL) by 13% (GMR: 0.87; 90% CI 41.95, 45.73; p = 0.019) of voriconazole. Conclusion: The alterations in PK parameters of voriconazole after concomitant administration of clarithromycin are of clinical significance. Therefore, adjustments in dosage regimens are warranted. In addition, extreme caution and therapeutic drug monitoring are necessary while co-prescribing both drugs. Clinical Trial Registration: clinicalTrials.gov, Identifier NCT05380245.

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

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

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