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

K. V
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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.
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卡维地洛(6.25和12.5 Mg片剂)在泰国健康志愿者体内的生物等效性和药代动力学
政府制药组织开发了卡维地洛12.5毫克和6.25毫克片剂的非专利产品,作为患者和医生的低成本替代品,以增强患者对长期用药的依从性和可及性。通过两项生物等效性研究,对卡维地洛12.5 mg片和6.25片的对照品进行生物等效性评价。两项研究的设计均为比较随机、开放标签、单剂量、双向交叉。采用有效的液相色谱串联质谱法同时测定血浆中卡维地洛和4′-羟基苯基卡维地洛(活性代谢物)的浓度。对卡维地洛和4′-羟基苯基卡维地洛进行药动学分析。用描述卡维地洛吸收速率和程度的药代动力学参数(AUC 0-tlast、AUC 0-∞和cmax)来判断受试品与参比品的生物等效性,并以4′-羟基苯基卡维地洛的药代动力学参数作为辅助信息。统计分析使用方差分析计算,两种配方之间没有显着差异。卡维地洛12.5 mg片的几何最小二乘平均比值(试验/参考)的90%置信区间分别为98.54 ~ 106.94%、98.54 ~ 106.56%和90.70 ~ 104.84%;卡维地洛6.25 mg片的几何最小二乘平均比值(试验/参考)的90%置信区间分别为95.56 ~ 105.99%、94.80 ~ 104.98%和92.00 ~ 107.33%。结果在80.00-125.00%的生物等效性标准范围内。因此,两种优势的仿制卡维地洛产品(Carvolol)在吸收速度和程度方面与创新产品(diltrend)具有生物等效性。在4′-羟基苯基卡维地洛中也观察到类似的结果,因此也可以预测试验制剂和参考制剂之间的治疗等效性。两项研究均未发现严重的不良事件。
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