Panchagnula Ramesh, Sancheti Pavankumar, Rungta Shradha, Agrawal Shrutidevi, Kaul Chaman Lal
Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Sector 67, 160062 Punjab, S.A.S. Nagar, India.
Pharmacol Res. 2003 Oct;48(4):383-7. doi: 10.1016/s1043-6618(03)00175-0.
The reliable supply of quality drugs in the form of fixed dose combination (FDC) is an essential part of tuberculosis treatment. The objective of this investigation was to evaluate whether the World Health Organization (WHO) simplified screening protocol for the bioequivalence assessment of rifampicin can be used for the evaluation of other components of FDC so as to ensure the bioavailability of all drugs at tissue site. These bioequivalence studies were conducted on 20 and 22 healthy male volunteers for evaluation of three and four drugs FDC formulations, respectively. Both studies were conducted as randomized, open, crossover trials and sampling schedule was upto 8h according to WHO recommended protocol for evaluation of rifampicin bioequivalence. The bioequivalence of isoniazid and pyrazinamide were estimated using AUC(0-8), AUC(0-alpha), and C(max). FDC formulation was considered bioequivalent to separate formulations for isoniazid and pyrazinamide if bioequivalence limit fall in between 0.80 and 1.25. Bioequivalence estimates of AUC(0-8) and AUC(0-alpha) for isoniazid and all the three pharmacokinetic measures of pyrazinamide were within the acceptable limits, whereas C(max) of isoniazid from four drugs FDC was outside the limit when evaluated by two-way ANOVA. After evaluation of isoniazid and pyrazinamide based on their pharmacokinetics, it was found that C(max) is being affected by limited sampling time points of WHO protocol. Further, AUC was a robust parameter unaffected by sampling schedule adopted. The WHO simplified protocol for assessment of rifampicin is also suitable for evaluating bioequivalence of isoniazid and pyrazinamide from FDC formulations. However, for comparison of rate of absorption by means of C(max), careful evaluation of concentration-time profile along with pharmacokinetics is necessary before final judgment.
以固定剂量复方制剂（FDC）形式提供的优质药品的可靠供应是结核病治疗的重要组成部分。本研究的目的是评估世界卫生组织（WHO）用于利福平生物等效性评估的简化筛查方案是否可用于评估FDC的其他成分，以确保所有药物在组织部位的生物利用度。这些生物等效性研究分别在20名和22名健康男性志愿者身上进行，以评估三种和四种药物的FDC制剂。两项研究均按照WHO推荐的利福平生物等效性评估方案进行随机、开放、交叉试验，采样时间长达8小时。使用AUC(0-8)、AUC(0-α)和C(max)评估异烟肼和吡嗪酰胺的生物等效性。如果生物等效性限度在0.80至1.25之间，则FDC制剂被认为与异烟肼和吡嗪酰胺的单独制剂具有生物等效性。异烟肼的AUC(0-8)和AUC(0-α)以及吡嗪酰胺的所有三种药代动力学指标的生物等效性估计值均在可接受范围内，而通过双向方差分析评估时，四种药物FDC中异烟肼的C(max)超出了限度。在根据药代动力学对异烟肼和吡嗪酰胺进行评估后，发现C(max)受到WHO方案有限采样时间点的影响。此外，AUC是一个不受所采用采样方案影响的稳健参数。WHO用于评估利福平的简化方案也适用于评估FDC制剂中异烟肼和吡嗪酰胺的生物等效性。然而，为了通过C(max)比较吸收速率，在最终判断之前，需要仔细评估浓度-时间曲线以及药代动力学。
