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 Following single and on the last day of the multiple dosing regimen, blood samples were withdrawn and serum concentrations of delapril and its metabolites M1, M2 and M3 and whole blood concentrations of indapamide were quantified by means of HPLC methods.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.

Liquid chromatography–tandem mass spectrometry validated method for the estimation of indapamide in human whole blood

“…These methods had LLOQ between 1.0 and 50.0 ng/ml, applicable for 2.5 mg, 5.0 mg of immediate release and 1.5 mg of sustainedrelease formulations. Many of these methods [8][9][10][11]14], however, do not meet some of the modern drug-development needs with respect to efficient extraction procedure, throughput or sufficient sensitivity. The capability of a single analytical method that encompasses all of the above merits to monitor the total absorption, distribution and elimination pharmacokinetic profile of the pre-clinical and clinical pharmacokinetic studies especially with low-dose sustained-release formulations is of prime concern.…”

“…The methods reported in literature for estimation of indapamide in whole blood [6,[8][9][10][11][12], serum [8,13,14], plasma [11,12], and urine [11,[15][16][17][18][19] involves use of HPLC, or in combination with MS, i.e. LC-MS/MS analytical techniques.…”

Simple, sensitive and rapid LC–MS method for the quantitation of indapamide in human plasma—application to pharmacokinetic studies

“…Although the assay of indapamide in pharmaceutical formulations and determination of the related substances profile is frequently referred in literature, using spectrometric and chromatographic [4][5][6][7] methods, only very few HPLC/UV methods were dedicated to its determination in biological fluids [8][9][10].…”

“…More often, liquid-liquid extraction procedures require two or three successive steps (extraction, backextraction, and re-extraction) [8,9] to eliminate matrix interferences. Moreover, ethyl acetate and diethyl ether were used as extracting phases.…”

Efficacy and Tolerability of Delapril Plus Indapamide Versus Lisinopril Plus Hydrochlorothiazide Combination Treatments in Mild to Moderate Hypertension: A Multicenter, Randomized Clinical Study

“…Compared with thiazide diuretics, indapamide appears to have less potassiumdepleting activity, and, in long-term therapy, it induces no negative effect on lipid or glucose metabolism. [9][10][11] Clinical trials [12][13][14][15][16][17] of the combination of delapril plus indapamide (DϩI) showed, both in case of single administration and at steady state, no interaction between the 2 components, and demonstrated its antihypertensive efficacy. The efficacy of this combination therapy in comparative studies 15,16 was significantly higher than that of the single components and was superior to that of captopril plus hydrochlorothiazide.…”