依非韦伦为基础的抗逆转录病毒治疗对合并结核分枝杆菌和人类免疫缺陷病毒感染患者利福平及其主要代谢物药代动力学的影响。

Effect of efavirenz-based ART on the pharmacokinetics of rifampicin and its primary metabolite in patients coinfected with TB and HIV.

机构信息

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.

出版信息

J Antimicrob Chemother. 2021 Oct 11;76(11):2950-2957. doi: 10.1093/jac/dkab258.

DOI:10.1093/jac/dkab258

PMID:34337654

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8521403/

Abstract

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.

摘要

目的

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。

患者与方法

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。

结果

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。