50mgdolutegravir和300mg拉米夫定的固定剂量组合(FDC)适用于治疗HIV-1感染。该分析旨在表征dolutegravir和拉米夫定的群体药代动力学(PK)基于3期研究(TANGO)在病毒学上抑制患有HIV-1转换为dolutegravir/拉米夫定FDC的成年人的数据。这些分析包括362名参与者,他们在48周内收集了2,629dolutegravir和2,611拉米夫定样品。通过表观口腔清除率(CL/F)参数化的一阶吸收和消除的单室模型,表观分布体积(V/F),和吸收速率常数(Ka)描述dolutegravirPK。协变量搜索产生体重,胆红素,和种族作为CL/F的预测因子,体重可预测V/F。CL/F的估计,V/F,Ka为0.858L/h,16.7L,和2.15h-1。由CL/F参数化的一阶吸收和消除的两室模型,表观室间间隙(Q/F),表观中心分布体积(V2/F),表观外周分布体积(V3/F),Ka描述了拉米夫定PK。协变量搜索产生eGFR和种族作为CL/F的预测因子,体重可预测V2/F。估计的参数值为CL/F=19.6L/h,Q/F=2.97L/h,V2/F=V3/F=105L,并且Ka=2.30h-1。稳态预测表明,协变量dolutegravir和拉米夫定暴露的影响很小(<20%),没有临床相关性。因此,根据这些分析,建议不进行剂量调整.结果支持使用dolutegravir/拉米夫定FDC治疗成人HIV-1感染。
结果:本研究在ClinicalTrials.gov注册为NCT03446573。
A fixed-dose combination (FDC) of 50 mg dolutegravir and 300 mg lamivudine is indicated for the treatment of HIV-1 infection. This analysis aimed to characterize the population pharmacokinetics (PK) of dolutegravir and lamivudine based on data from a phase 3 study (TANGO) in virologically suppressed adults living with HIV-1 switching to dolutegravir/lamivudine FDC. These analyses included 362 participants who contributed 2,629 dolutegravir and 2,611 lamivudine samples collected over 48 weeks. A one-compartment model with first-order absorption and elimination parameterized by apparent oral clearance (CL/F), apparent volume of distribution (V/F), and absorption rate constant (Ka) described dolutegravir PK. Covariate search yielded body weight, bilirubin, and ethnicity as predictors of CL/F, and weight was predictive for V/F. The estimates of CL/F, V/F, and Ka were 0.858 L/h, 16.7 L, and 2.15 h-1, respectively. A two-compartment model with first-order absorption and elimination parameterized by CL/F, apparent intercompartmental clearance (Q/F), apparent central volume of distribution (V2/F), apparent peripheral volume of distribution (V3/F), and Ka described lamivudine PK. Covariate search yielded eGFR and race as predictors of CL/F, and weight was predictive for V2/F. The estimated parameter values were CL/F = 19.6 L/h, Q/F = 2.97 L/h, V2/F = V3/F = 105 L, and Ka = 2.30 h-1. The steady-state prediction suggested that the effect of covariates dolutegravir and lamivudine exposures was small (<20%) and not clinically relevant. Therefore, no dose adjustments are recommended based on these analyses. The results support the use of dolutegravir/lamivudine FDC in the treatment of HIV-1 infection in adults.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT03446573.