Objectives To evaluate the effects of concomitant efavirenz-based ART and genetic polymorphism on the variability in rifampicin and 25-desacetylrifampicin pharmacokinetics. Patients and methods Plasma concentrations of rifampicin and 25-desacetylrifampicin from 63 patients coinfected with TB and HIV were analysed by LC-MS/MS followed by non-linear mixed-effects modelling. Patients were genotyped for SLCO1B1 (463 C>A, 388 A>G, 11187 G>A, rs4149015, 521 T>C and 1436 G>C) and SLCO1B3 (334 T>G). Results One-compartment disposition models described the observations adequately. The oral clearances of rifampicin and 25-desacetylrifampicin were 140% and 110% higher, respectively, in patients on concomitant efavirenz-based ART. Rifampicin bioavailability was also lower in patients on concomitant ART. Further, although not included in the final model, a lower relative bioavailability in carriers of WT SLCO1B3 334 T>G compared with carriers of mutations in the genotype was estimated. Conclusions The results presented indicate both pre-systemic and systemic induction by efavirenz-based ART affecting rifampicin pharmacokinetics. The described drug–drug interaction has a clinical impact on rifampicin exposure prior to steady state and may impact the early bactericidal activity in patients on efavirenz-based ART.

中文翻译：

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基于依非韦伦的抗逆转录病毒疗法对结核病和艾滋病毒合并感染患者利福平及其主要代谢物药代动力学的影响

目的 评估伴随依非韦伦为基础的 ART 和基因多态性对利福平和 25-去乙酰基利福平药代动力学变异性的影响。患者和方法 通过 LC-MS/MS 分析来自 63 名合并感染 TB 和 HIV 的患者的利福平和 25-去乙酰基利福平的血浆浓度，然后进行非线性混合效应建模。对患者进行 SLCO1B1（463 C>A、388 A>G、11187 G>A、rs4149015、521 T>C 和 1436 G>C）和 SLCO1B3（334 T>G）的基因分型。结果 一室配置模型充分描述了观察结果。在同时接受基于依非韦伦的 ART 的患者中，利福平和 25-去乙酰利福平的口服清除率分别高出 140% 和 110%。在同时接受 ART 的患者中，利福平的生物利用度也较低。进一步，尽管未包括在最终模型中，但估计与基因型突变的携带者相比，WT SLCO1B3 334 T>G 携带者的相对生物利用度较低。结论 所呈现的结果表明基于依非韦伦的 ART 的全身性和全身性诱导都会影响利福平的药代动力学。所描述的药物-药物相互作用对稳态前的利福平暴露具有临床影响，并可能影响基于依非韦伦的 ART 患者的早期杀菌活性。