Clinical Pharmacology Modeling & Simulation, GSK, Collegeville, Pennsylvania, USA.
ViiV Healthcare, Durham, North Carolina, USA.
Antimicrob Agents Chemother. 2024 May 2;68(5):e0150423. doi: 10.1128/aac.01504-23. Epub 2024 Apr 8.
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, 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. 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.
一种固定剂量组合（FDC），即 50 毫克多替拉韦和 300 毫克拉米夫定，被批准用于治疗 HIV-1 感染。本分析旨在根据一项 3 期研究（TANGO）的数据，对多替拉韦和拉米夫定的群体药代动力学（PK）进行特征描述，该研究涉及接受 HIV-1 病毒抑制治疗的成年人转换为多替拉韦/拉米夫定 FDC。这些分析包括 362 名参与者，他们在 48 周内共提供了 2629 份多替拉韦和 2611 份拉米夫定样本。一个一室模型，采用一级吸收和消除，参数为表观口服清除率（CL/F）、表观分布容积（V/F）和吸收速率常数（Ka），描述了多替拉韦 PK。协变量搜索结果表明体重、胆红素和种族是 CL/F 的预测因子，而体重是 V/F 的预测因子。CL/F、V/F 和 Ka 的估计值分别为 0.858 L/h、16.7 L 和 2.15 h。一个两室模型，采用一级吸收和消除，参数为 CL/F、表观隔室间清除率（Q/F）、表观中央分布容积（V2/F）、表观外周分布容积（V3/F）和 Ka，描述了拉米夫定 PK。协变量搜索结果表明 eGFR 和种族是 CL/F 的预测因子，而体重是 V2/F 的预测因子。估计的参数值为 CL/F = 19.6 L/h、Q/F = 2.97 L/h、V2/F = V3/F = 105 L 和 Ka = 2.30 h。稳态预测表明，多替拉韦和拉米夫定暴露的协变量对药物暴露的影响较小（<20%），且无临床意义。因此，根据这些分析，不建议调整剂量。研究结果支持多替拉韦/拉米夫定 FDC 用于治疗成人 HIV-1 感染。临床试验本研究在 ClinicalTrials.gov 注册为 NCT03446573。
