Investigation of bioequivalence of a new-fixed-dose-combination-of- nifedipine-and-candesartan with the corresponding loose combination as well as the drug-drug interaction potential between both drugs under fasting conditions

摘要

Objective: To determine the bioequivalence of a nifedipine and cande-sartan fixed-dose combination (FDC) with the corresponding loose combination, and to investigate the pharmacokinetic drug-drug interaction potential between both drugs. Methods: 49 healthy, white, male subjects received: 60 mg nifedipine and 32 mg cande-sartan FDC, the loose combination of 60 mg nifedipine GITS and 32 mg candesartan, 60 mg nifedipine GITS alone, or 32 mg can-desartan alone in a randomized, non-blinded, 4-period, 4-way crossover design with each dosing following overnight fasting. Treatment periods were separated by washout periods of 5 days. Plasma samples were collected for 48 hours after dosing and assayed using a validated LC-MS/MS method. Results: Bioequivalence between the FDC and the loose combination as well as the impact of combined treatment with both drugs on candesartan pharmacokinetics was evaluated in 47 subjects, while the corresponding impact of treatment with both drugs on nife-dipine pharmacokinetics was assessed in 46 patients. For AUC(0-tlast) and Cmax the 90% confidence intervals (CIs) for the ratios of the FDC vs. the corresponding loose combination were within the acceptance range for bioequivalence of 80-125%. When comparing AUC(0-tlast) and C max of nifedipine and candesartan after dosing with the loose combination vs. each drug alone, the 90% CIs remained within the range of 80-125% indicating the absence of a clinically relevant pharmacokinetic drug-drug interaction. Nife-dipine and candesartan as well as the combinations were well tolerated. Conclusions: The FDC containing 60 mg nifedipine and 32 mg candesartan was bioequivalent to the corresponding loose combination following single oral doses under fasting conditions. No clinically relevant pharmacokinetic drug-drug interaction between nifedipine and can-desartan was observed.