Zhu Hui, Guo Shao-Chen, Hao Lan-Hu, Liu Cheng-Cheng, Wang Bin, Fu Lei, Chen Ming-Ting, Zhou Lin, Chi Jun-Ying, Yang Wen, Nie Wen-Juan, Lu Yu
Department of Pharmacology, Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumour Research Institute, Beijing 101149, China.
Chin Med J (Engl). 2015 Feb 20;128(4):433-7. doi: 10.4103/0366-6999.151061.
Decreases in the bioavailability of rifampicin (RFP) can lead to the development of drug resistance and treatment failure. Therefore, we investigated the relative bioavailability of RFP from one four-drug fixed-dose combination (FDC; formulation A) and three two-drug FDCs (formulations B, C, and D) used in China, compared with RFP in free combinations of these drugs (reference), in healthy volunteers.
Eighteen and twenty healthy Chinese male volunteers participated in two open-label, randomized two-period crossover (formulations A and C) or one three-period crossover (formulations B and D) study, respectively. The washout period between treatments was 7 days. Bioequivalence was assessed based on 90% confidence intervals, according to two one-sided t-tests. All analyses were done with DAS 3.1.5 (Mathematical Pharmacology Professional Committee of China, Shanghai, China).
Mean pharmacokinetic parameter values of RFP obtained for formulations A, B, C, and D products were 11.42 ± 3.41 μg/ml, 7.86 ± 5.78 μg/ml, 13.05 ± 6.80 μg/ml, and 16.18 ± 3.87 μg/ml, respectively, for peak plasma concentration (C max ), 91.43 ± 30.82 μg·h-1·ml-1 , 55.49 ± 37.58 μg·h-1·ml-1 , 96.50 ± 47.24 μg·h-1·ml-1 , 101.47 ± 33.07 μg·h-1·ml-1 , respectively, for area under the concentration-time curve (AUC 0-24 h ).
Although the concentrations of RFP for formulations A, C, and D were within the reported acceptable therapeutic range, only formulation A was bioequivalent to the reference product. The three two-drug FDCs (formulations B, C and D) displayed inferior RFP bioavailability compared with the reference (Chinese Clinical Trials registration number: ChiCTR-TTRCC-12002451).
利福平（RFP）生物利用度降低可导致耐药性产生及治疗失败。因此，我们在中国健康志愿者中研究了一种四联固定剂量复方制剂（FDC；制剂A）和三种二联FDC（制剂B、C和D）中RFP的相对生物利用度，并与这些药物的自由组合（参比制剂）中的RFP进行比较。
18名和20名健康中国男性志愿者分别参与了两项开放标签、随机两周期交叉试验（制剂A和C）或一项三周期交叉试验（制剂B和D）。各治疗之间的洗脱期为7天。根据两个单侧t检验，基于90%置信区间评估生物等效性。所有分析均使用DAS 3.1.5（中国上海中国数学药理专业委员会）进行。
制剂A、B、C和D产品的RFP平均药代动力学参数值，峰血浆浓度（Cmax）分别为11.42±3.41μg/ml、7.86±5.78μg/ml、13.05±6.80μg/ml和16.18±3.87μg/ml，浓度-时间曲线下面积（AUC0-24h）分别为91.43±30.82μg·h-1·ml-1、55.49±37.58μg·h-1·ml-1、96.50±47.24μg·h-1·ml-1和101.47±33.07μg·h-1·ml-1。
虽然制剂A、C和D的RFP浓度在报道的可接受治疗范围内，但只有制剂A与参比制剂生物等效。与参比制剂相比，三种二联FDC（制剂B、C和D）的RFP生物利用度较差（中国临床试验注册号：ChiCTR-TTRCC-12002451）。
