Bioavailability and pharmacokinetics of a fixed combination of delapril/indapamide following single and multiple dosing in healthy volunteers.

Abstract

The study objective was to obtain detailed information on the bioavailability and pharmacokinetics of the new fixed combination of delapril and indapamide following single and multiple dosing. For this reason, the study was performed in two parts, separated by a medication-free period of at least 7 days. In the single dose part, one tablet, containing 30 mg delapril and 2.5 mg indapamide, was administered to 12 male volunteers; in the multiple dose part, the volunteers received one tablet of the test preparation, once daily over 7 days. Following single and on the last day of the multiple dosing regimen, blood samples were withdrawn and serum concentrations of delapril and its metabolites M1, M2 and M3 and whole blood concentrations of indapamide were quantified by means of HPLC methods. In addition, urine samples were collected following single and multiple dosing for evaluation of the cumulative amount of delapril and its metabolites M1-M3 excreted in urine. For the area under the curve, calculated from time 0 to infinity (AUC(0-infinity)) the study revealed, following single dosing, mean values of delapril and its metabolites M1, M2 and M3 of 281, 2178, 739 and 716 h.ng/ml, respectively; for indapamide the mean value was 1597 h.ng/ml. The corresponding mean values found after multiple dose administration were 272, 2071, 857 and 598 h.ng/ml for delapril and its metabolites, respectively and 1536 h.ng/ml for indapamide. Evaluation of the cumulative amount of delapril and its metabolites M1-M3 excreted in urine (Ae) demonstrated mean values following single dosing (observation period 36 h) of 705, 4521, 454 and 4203 micrograms, respectively; the corresponding values after multiple dose administration (observation period 24 h) of the test preparation were 655, 4679, 469 and 4801 micrograms, respectively. The most important pharmacokinetic parameters AUC(0-infinity) and Ae were statistically compared by analysis of variance (ANOVA) and 90% confidence intervals were calculated. It may be concluded from the results of this study, that the bioavailability and pharmacokinetic parameters of the test preparation after single dosing and after multiple doses correspond well. The undesired side effects observed are known to occur after administration of the test preparation. The occurrence was a little more frequent after multiple dose application in comparison with the single dose administration.