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.
Stockis
Armel
A
SGS Biopharma S.A., Wavre, Belgium.
Gengler
Christophe
C
Goethals
Fabienne
F
Jeanbaptiste
Bernard
B
Lens
Simone
S
Poli
Gianluigi
G
Acerbi
Daniela
D
D000328:Adult; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D002121:Calcium Channel Blockers / Q000009:adverse effects / Q000493:pharmacokinetics*; D002853:Chromatography, Liquid; D018592:Cross-Over Studies; D004095:Dihydropyridines / Q000009:adverse effects / Q000493:pharmacokinetics*; D004338:Drug Combinations; D004347:Drug Interactions; D006207:Half-Life; D006801:Humans; D007189:Indans / Q000009:adverse effects / Q000493:pharmacokinetics*; D008297:Male; D013058:Mass Spectrometry; D009578:Nitrobenzenes; D010879:Piperazines
D000806:Angiotensin-Converting Enzyme Inhibitors; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D004338:Drug Combinations; D007189:Indans; D009578:Nitrobenzenes; D010879:Piperazines; C054218:manidipine; C047759:delapril