Bioavailability study of fixed-dose tablet versus capsule formulation of amlodipine plus benazepril: A randomized, single-dose, two-sequence, two-period, open-label, crossover study in healthy volunteers

Abstract

Background: In the treatment of hypertension, combination therapy is important10 because antihypertensive monotherapy is effective in only 40% of patients worldwide. Amlodipine is a dihydropyridine calcium channel blocker with a slow onset and long duration of action. Benazepril hydrochloride is a prodrug hydrolyzed by esterase to the active metabolite benazeprilat, an angiotensin-converting enzyme inhibitor. In 1995, the US Food and Drug Administration approved the use of a capsule formulation of combination amlodipine-benazepril for hypertension.

Objective: The aim of this study was to compare the bioavailability and tolerability10 of the capsule formulation with those of a tablet formulation of combination amlodipine-benazepril in healthy volunteers.

Methods: This single-dose, 2-sequence, 2-period, open-label, crossover10 study recruited healthy, adult, male volunteers with normotension. Subjects were randomly assigned to 1 of 2 treatment sequences: a single-dose tablet containing amlodipine 5 mg plus benazepril 10 mg, followed by a single-dose capsule containing the same dose of each drug (AB), or vice versa (BA). The treatment period for each drug consisted of dosing and pharmacokinetic analysis on day 1, followed by pharmacokinetic analysis on days 2 to 7. Treatment periods were separated by a 4-week washout period. For pharmacokinetic analysis, serial blood samples were obtained before dosing and at 20, 40, 60, 80, and 100 minutes and 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 36, 60, 84, 108, 132, and 156 hours after dosing. Tolerability was assessed using subject interview and spontaneous reporting.

Results: Twelve healthy, male, Taiwanese subjects (mean [SD] age, 23.510 [1.7] years) participated in the study. No statistically significant differences inbioavailability were found between the 2 formulations based on the pharmacokinetic measurements of amlodipine and benazeprilat. The rate and extent of absorption of the tablets were found to be comparable to those of the capsules (90% CI, between 80% and 125%). The mean (SD) relative bioavailabilities, as represented by AUC0-∞, of amlodipine and benazeprilat for tablets versus capsules were 1.060 (0.170) versus 0.949 (0.197), respectively. The mean plasma concentration-time profiles of amlodipine and benazeprilat were graphically similar. No adverse effects were observed with either formulation.

Conclusions: The results of this bioavailability comparison study in this 10 population of healthy, male, Taiwanese volunteers suggest that the tablet and capsule formulations of combination amlodipine-benazepril are bioequivalent. Both formulations were well tolerated.

Keywords: amlodipinebesylate; benazepril hydrochloride; bioavailability; bioequivalence; fixed-dose combination; pharmacokinetics.