多替拉韦 100 毫克每日一次与利福平合用的药代动力学。

Pharmacokinetics of dolutegravir 100 mg once daily with rifampicin.

机构信息

Jefferiss Research Trust Laboratories, Department of Medicine, Imperial College London, London, UK.

St. Stephen's Centre, Chelsea and Westminster Hospital, London, UK.

出版信息

Int J Antimicrob Agents. 2019 Aug;54(2):202-206. doi: 10.1016/j.ijantimicag.2019.04.009. Epub 2019 Apr 16.

DOI:10.1016/j.ijantimicag.2019.04.009

PMID:31002950

Abstract

BACKGROUND

Tuberculosis (TB) causes 25% of all deaths among individuals infected with human immunodeficiency virus (HIV). Rifampicin (RIF) is a potent inducer of drug metabolizing enzymes and drug transporters, and co-administration with dolutegravir (DTG) reduces DTG exposure; this can be overcome by doubling the DTG dose to 50 mg twice daily. This study investigated the effect of RIF on DTG exposure when dosed at 100 mg once daily, which could provide an easier option than 50 mg twice daily.

METHODS

An open label, pharmacokinetic (PK) study was undertaken. Healthy HIV-negative subjects received DTG 50 mg for 7 days (PK1), DTG 100 mg for 7 days (PK2), RIF for 14 days, DTG 50 mg + RIF for 7 days (PK3) and DTG 100 mg + RIF for 7 days (PK4). Steady-state full DTG PK profiles were evaluated.

RESULTS

DTG geometric mean ratios (GMRs) of PK3/PK1 of maximum concentration (C), area under curve (AUC) and 24-h post-dose concentration (C) were 0.65 [90% confidence interval (CI) 0.55-0.75], 0.44 (90% CI 0.37-0.52) and 0.15 (0.13-90% CI 0.17), respectively. GMRs of PK4/PK1 C, AUC and C were 1.09 (90% CI 0.97-1.21), 0.74 (90% CI 0.64-0.86) and 0.24 (90% CI 0.20-0.28), respectively. Median C of DTG 50 mg + RIF and DTG 100 mg + RIF were 251 (range 129-706) ng/mL and 140 (range 73-426) ng/mL, respectively.

CONCLUSION

Although there were substantial reductions in DTG C when co-administered with RIF, concentrations of both DTG 50 mg and 100 mg once daily with RIF were still above the protein-binding-adjusted IC (drug concentration required to inhibit 90% of in-vitro viral replication) of 64 ng/mL. Further studies in HIV-TB co-infected individuals are warranted to confirm these results.

摘要

背景

结核病（TB）导致 25%感染人类免疫缺陷病毒（HIV）的个体死亡。利福平（RIF）是一种有效的药物代谢酶和药物转运体诱导剂，与多替拉韦（DTG）联合用药会降低 DTG 暴露量；通过将 DTG 剂量加倍至每日两次，每次 50 毫克，可以克服这种情况。本研究旨在研究 RIF 对每日一次 100 毫克 DTG 暴露量的影响，这可能比每日两次 50 毫克的方案更容易。

方法

这是一项开放标签、药代动力学（PK）研究。健康的 HIV 阴性受试者接受 DTG 50 毫克，连续 7 天（PK1）；DTG 100 毫克，连续 7 天（PK2）；RIF 治疗 14 天；DTG 50 毫克+RIF 治疗 7 天（PK3）；DTG 100 毫克+RIF 治疗 7 天（PK4）。评估稳态全 DTG PK 谱。

结果

PK3/PK1 的 DTG 几何均数比值（GMR）最大浓度（C）、曲线下面积（AUC）和 24 小时后浓度（C）分别为 0.65 [90%置信区间（CI）0.55-0.75]、0.44（90% CI 0.37-0.52）和 0.15（0.13-90% CI 0.17）。PK4/PK1 的 GMR C、AUC 和 C 分别为 1.09（90% CI 0.97-1.21）、0.74（90% CI 0.64-0.86）和 0.24（90% CI 0.20-0.28）。DTG 50 毫克+RIF 和 DTG 100 毫克+RIF 的中位 C 分别为 251（范围 129-706）ng/ml 和 140（范围 73-426）ng/ml。