Bioequivalence study of two different tablet formulations of carvedilol in healthy volunteers.
ABSTRACT The aim of this study was to compare the extent and rate of absorption of two different carvedilol (CAS 72956-09-3) tablet formulations: 25 mg tablets, as the test formulation and the reference innovator product (25 mg tablets).
This study was designed as a single-dose, open-label, randomised, with a two-period and two-sequence crossover design, with blind determination of drug plasma concentration and a minimum 7-day washout period. Twenty-four healthy volunteers of both sexes were randomly assigned to treatment sequences. Carvedilol concentrations were determined in plasma samples obtained over a 24-h interval: baseline (pre-administration) and at 14 different times within the 24 h after administration. The analytical method, which used HPLC coupled with a MS/MS detector, was duly validated and the analytical assay was performed in compliance with Good Laboratory Practice (GLP). The limit of quantification (LOQ) was 0.50 ng/mL. Pharmacokinetic parameters representing the extent and/or rate of absorption (AUCinf, AUClast, and Cmax) were obtained. As secondary objective the tolerability of both formulations was also evaluated.
The geometric mean of the test/reference formulations individual percent ratio was 98.14 % for AUCinf, 98.44 % for AUClast and 98.39 % for Cmax. The 90 % CI for the geometric mean of the individual ratio test/references formulations was 95.13 to 101.24 % for AUCinf, 95.23 to 101.76 % for AUClast, and 88.26 to 109.67 % for Cmax.
The 90 % CI values obtained for AUCinf, AUClast, and Cmax are within the interval proposed by the EMEA/CPMP and the FDA as bioequivalence acceptance criteria, and consequently it can be conclude that the test formulation is bioequivalent with the reference formulation both in terms of rate and extent of absorption after single dose administration. The results from a previous pilot study allowed an optimal design for this trial.
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ABSTRACT: Use of generic drugs, which are bioequivalent to brand-name drugs, can help contain prescription drug spending. However, there is concern among patients and physicians that brand-name drugs may be clinically superior to generic drugs. To summarize clinical evidence comparing generic and brand-name drugs used in cardiovascular disease and to assess the perspectives of editorialists on this issue. Systematic searches of peer-reviewed publications in MEDLINE, EMBASE, and International Pharmaceutical Abstracts from January 1984 to August 2008. Studies compared generic and brand-name cardiovascular drugs using clinical efficacy and safety end points. We separately identified editorials addressing generic substitution. We extracted variables related to the study design, setting, participants, clinical end points, and funding. Methodological quality of the trials was assessed by Jadad and Newcastle-Ottawa scores, and a meta-analysis was performed to determine an aggregate effect size. For editorials, we categorized authors' positions on generic substitution as negative, positive, or neutral. We identified 47 articles covering 9 subclasses of cardiovascular medications, of which 38 (81%) were randomized controlled trials (RCTs). Clinical equivalence was noted in 7 of 7 RCTs (100%) of beta-blockers, 10 of 11 RCTs (91%) of diuretics, 5 of 7 RCTs (71%) of calcium channel blockers, 3 of 3 RCTs (100%) of antiplatelet agents, 2 of 2 RCTs (100%) of statins, 1 of 1 RCT (100%) of angiotensin-converting enzyme inhibitors, and 1 of 1 RCT (100%) of alpha-blockers. Among narrow therapeutic index drugs, clinical equivalence was reported in 1 of 1 RCT (100%) of class 1 antiarrhythmic agents and 5 of 5 RCTs (100%) of warfarin. Aggregate effect size (n = 837) was -0.03 (95% confidence interval, -0.15 to 0.08), indicating no evidence of superiority of brand-name to generic drugs. Among 43 editorials, 23 (53%) expressed a negative view of generic drug substitution. Whereas evidence does not support the notion that brand-name drugs used in cardiovascular disease are superior to generic drugs, a substantial number of editorials counsel against the interchangeability of generic drugs.JAMA The Journal of the American Medical Association 01/2009; 300(21):2514-26. · 29.98 Impact Factor