Unit for Pharmacokinetics and Drug Metabolism, Department of Pharmacology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
Department of Pharmacy, School of Medicine and Pharmacy, University of Rwanda, Rwanda.
J Antimicrob Chemother. 2021 Oct 11;76(11):2950-2957. doi: 10.1093/jac/dkab258.
To evaluate the effects of concomitant efavirenz-based ART and genetic polymorphism on the variability in rifampicin and 25-desacetylrifampicin pharmacokinetics.
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).
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.
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.
评估同时使用依非韦伦为基础的抗逆转录病毒治疗（ART）和遗传多态性对利福平及 25-去乙酰利福平药代动力学变异性的影响。
采用 LC-MS/MS 法对 63 例合并结核分枝杆菌（TB）和人类免疫缺陷病毒（HIV）感染的患者的血浆利福平及 25-去乙酰利福平浓度进行分析，并用非线性混合效应模型进行分析。对 SLCO1B1（463 C>A、388 A>G、11187 G>A、rs4149015、521 T>C 和 1436 G>C）和 SLCO1B3（334 T>G）进行基因分型。
单室模型能充分描述观察结果。同时使用依非韦伦为基础的 ART 的患者，利福平及 25-去乙酰利福平的口服清除率分别提高了 140%和 110%。同时使用 ART 的患者利福平生物利用度也较低。此外，尽管未纳入最终模型，但估计携带 WT SLCO1B3 334 T>G 的患者相对生物利用度低于基因型突变携带者。
本研究结果表明，依非韦伦为基础的 ART 同时具有前体系统和全身诱导作用，影响利福平的药代动力学。所描述的药物相互作用对稳态前利福平的暴露有临床影响，可能会影响依非韦伦为基础 ART 治疗患者的早期杀菌活性。
