Single oral dose pharmacokinetic interaction study of manidipine and delapril in healthy volunteers.

OBJECTIVE: The objective of the study was to assess potential pharmacokinetic interactions between delapril, an angiotensin conversion enzyme inhibitor, and manidipine, a calcium channel antagonist, prior to the development of a fixed combination drug product.

METHODS: Eighteen healthy male volunteers received a single oral dose of 10 mg manidipine dihydrochloride (CAS 89226-75-5), or 30 mg delapril hydrochloride (CAS 83435-67-0), or both simultaneously, according to a fully balanced three-way cross-over design. The three treatments were separated by a one-week washout period. Blood samples were collected during 24 h for plasma determination of manidipine and metabolite M-XIII and/or of delapril and metabolites M1, M2 and M3, using specific LCMS/MS methods.

RESULTS: The bioavailability of manidipine and M-XIII was slightly decreased by concomitant administration of delapril (manidipine: Cmax-19% and AUC infinity-11% M-XIII: Cmax-17% and AUCt-18%). The bioavailability of delapril was not influenced by co-administration with manidipine (Cmax-7% and AUC infinity +4%). The effect on delapril pharmacologically active metabolites M1 and M3 was negligible. The inactive metabolite M2 underwent a 13% reduction of Cmax and AUC infinity. The 90% confidence intervals were confined within limits of acceptance (70-143% for Cmax and 80-125% for AUC). Mean residence times and apparent elimination half-lives were unaltered. Blood pressure and heart rate versus time profiles were similar during the three treatments.

CONCLUSIONS: Simultaneous oral administration of 10 mg manidipine and 30 mg delapril does not significantly alter the pharmacokinetics of either drug or that of their principal metabolites.