Pharmacokinetic interaction between bedaquiline and clofazimine in patients with drug-resistant tuberculosis
Pharmacokinetic interaction between bedaquiline and clofazimine in patients with drug-resistant tuberculosis
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DOI：
10.5588/ijtld.17.0615
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发表时间：
2018-01-01
影响因子：
4
通讯作者：
Svensson, E. M.
中科院分区：
文献类型：
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作者：
Maartens, G.;Brill, M. J. E.;Svensson, E. M.
背景：贝达喹啉（BDQ）和氯法齐明（CFZ）均被推荐用于治疗耐药结核病（DR-TB）。由于CFZ在体外是细胞色素P450同工酶3A 4（CYP 3A 4）的抑制剂，而BDQ是CYP 3A 4的底物，因此当与CFZ联合给药时，存在药代动力学（PK）药物相互作用的可能性，可能导致BDQ暴露增加，这可能增加BDQ的毒性。我们使用根据DR-TB患者数据开发的群体PK模型，评估了在DR-TB患者中联合给予CFZ对BDQ生物利用度或对BDQ及其N-单去甲基代谢物（M2）清除率的影响。这是一项旨在探讨BDQ和抗逆转录病毒药物之间的药物相互作用的研究的二次分析。结果：46名参与者中，30人在进行密集的BDQ PK采样时同时使用CFZ。CFZ对BDQ生物利用度没有统计学显著影响（-9.1%，90%CI- 22.8至+7.1; P = 0.19）或BDQ和M2清除率（+12.2%，90%CI-13.7至+38; P = 0.32）。结论：我们未发现BDQ和CFZ之间存在统计学显著的PK药物-药物相互作用，但由于估计的相互作用效应的置信区间较宽，因此无法排除潜在的临床相关相互作用。
BACKGROUND: Bedaquiline (BDQ) and clofazimine (CFZ) are both recommended for treating drug-resistant tuberculosis (DR-TB). As CFZ is an inhibitor of the cytochrome P450 isoenzyme 3A4 (CYP3A4) in vitro, and BDQ a substrate of CYP3A4, there is a potential for pharmacokinetic (PK) drug-drug interaction that may result in increased BDQ exposure when co-administered with CFZ, which could increase the toxicity of BDQ.METHODS : We assessed the effect of co-administered CFZ on BDQ bioavailability, or on clearance of BDQ and its N-monodesmethyl metabolite (M2), in patients with DR-TB using a population PK model developed from data of patients with DR-TB. This was a secondary analysis of a study designed to explore drug-drug interactions between BDQ and antiretrovirals.RESULTS : Of 46 participants, 30 were on concomitant CFZ when intensive PK sampling of BDQ was done. CFZ did not have a statistically significant effect on BDQ bioavailability (-9.1%, 90% CI - 22.8 to +7.1; P = 0.19) or on BDQ and M2 clearance (+12.2%, 90% CI -13.7 to +38; P = 0.32).CONCLUSION: We did not find a statistically significant PK drug-drug interaction between BDQ and CFZ, but cannot exclude a potentially clinically relevant interaction due to the wide confidence intervals of the estimated interaction effects.