Evaluation of the bioequivalence of two formulations containing the combination of 400 mg of acetaminophen (paracetamol), 4 mg of phenylephrine and 4 mg of chlorpheniramine in capsules: open-label, three-way crossover study, partially replicated in healthy volunteers of both sexes

This study was carried out in order to compare the relative bioavailability of two different formulations containing 400 mg of acetaminophen + 4 mg of phenylephrine hydrochloride + 4 mg of chlorpheniramine maleate, Test formulation (Cimegripe®) and Reference formulation (Resfenol®) in 84 healthy volunteers of both sexes under fasting conditions. The study was conducted in a single dose, randomized, open-label, crossover 3-way and partially replicated. The tolerability was evaluated by the monitoring of adverse events and vital signs, results of clinical and laboratory tests. Plasma concentrations were quantified by validated bioanalytical methods using the ultra-performance liquid chromatography coupled to tandem mass spectrometry. The Cmax, Tmax, AUC0-t, AUC0-inf, T1/2 and Kel pharmacokinetic parameters were calculated from these obtained concentrations. The 90% confidence intervals were constructed for the ratio reference/test from the geometric average of the Cmax and AUC parameters which were comprised between 80% and 125%. Only the Cmax parameter of the phenylephrine was applied the scaled average bioequivalence due to the intraindividual coefficient of variation > 30% obtained, thus extending the acceptance limits of the interval. It can be concluded that the two formulations were bioequivalent in terms of rate and absorption extent and thus interchangeable.

本研究旨在比较两种含400mg对乙酰氨基酚+4mg盐酸去氧肾上腺素+4mg马来酸氯苯那敏的制剂的相对生物利用度，分别为试验制剂（Cimegripe®）与参比制剂（Resfenol®），研究对象为84名男女健康受试者，试验在空腹条件下开展。本研究采用单剂量、随机、开放标签、三周期交叉且部分重复的试验设计。耐受性通过不良事件监测、生命体征评估以及临床与实验室检查结果进行评价。血浆浓度采用经验证的生物分析方法进行定量，该方法采用超高效液相色谱-串联质谱法（ultra-performance liquid chromatography coupled to tandem mass spectrometry）。基于测得的血浆浓度，计算得到Cmax、Tmax、AUC0-t、AUC0-inf、T1/2及Kel等药代动力学参数。以参比制剂/试验制剂的几何均值构建90%置信区间，其中Cmax与AUC参数的置信区间需处于80%~125%的范围内。由于测得的个体内变异系数＞30%，仅针对去氧肾上腺素的Cmax参数采用缩放平均生物等效性（scaled average bioequivalence），以放宽该参数的置信区间接受限度。最终可得出结论：两种制剂在吸收速率与吸收程度方面均具有生物等效性，因此可互换使用。