Bioequivalence and Pharmacokinetics of Carvedilol (6.25 and 12.5 Mg Tablets) in Healthy Thai Volunteers

Abstract

The Government Pharmaceutical Organization (GPO) had developed the generic products of carvedilol 12.5 and 6.25 mg tablets as low-cost alternatives for patients and physicians to enhance patient adherence and accessibility to long-term use medications. Two bioequivalence studies were conducted to evaluate the bioequivalence between the test and reference products of carvedilol 12.5 mg and 6.25 tablets. The design for both studies was comparative randomized, open-label, single- dose, two-way crossover. Carvedilol and 4′-hydroxyphenyl carvedilol (active metabolite) concentrations in plasma were simultaneously determined by a validated liquid chromatography tandem mass spectrometry method. The pharmacokinetic analysis was carried out for carvedilol and 4′-hydroxyphenyl carvedilol. The pharmacokinetic parameters describing the rate and extent of absorption of carvedilol (AUC 0-tlast , AUC 0-∞ and C max ) were used to conclude the bioequivalence between the test and reference products whereas the pharmacokinetic parameters of 4′-hydroxyphenyl carvedilol were presented as supportive information. The statistical analysis was calculated using an analysis of variance and did not show any significant difference between the two formulations. The 90% confidence intervals of the geometric least squares mean ratios (test/ reference) of ln-transformed AUC 0-tlast , AUC 0-∞ and C max were 98.54-106.94%, 98.54-106.56% and 90.70-104.84%, respectively for carvedilol 12.5 mg tablets, and 95.56-105.99%, 94.80-104.98% and 92.00-107.33%, respectively for carvedilol 6.25 mg tablets. The results were well within 80.00-125.00% corresponding to the bioequivalence criteria. Therefore, the generic carvedilol products (Carvolol) at both strengths are bioequivalent with the innovator products (Dilatrend) in terms of rate and extent of absorption. Similar findings were observed for 4′-hydroxyphenyl carvedilol, thus therapeutic equivalence between the test and reference formulations could also be anticipated. The products were well tolerated by the study subjects and no serious adverse events were reported in both studies.