Population pharmacokinetic modeling of dolutegravir/lamivudine to support a once-daily fixed-dose combination regimen in virologically suppressed adults living with HIV-1.

Autor:	Chandasana H; Clinical Pharmacology Modeling & Simulation, GSK, Collegeville, Pennsylvania, USA., Singh R; Clinical Pharmacology Modeling & Simulation, GSK, Collegeville, Pennsylvania, USA., Adkison K; ViiV Healthcare, Durham, North Carolina, USA., Ait-Khaled M; ViiV Healthcare Ltd., Brentford, United Kingdom., Pene Dumitrescu T; Clinical Pharmacology Modeling & Simulation, GSK, Collegeville, Pennsylvania, USA.
Jazyk:	angličtina
Zdroj:	Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2024 May 02; Vol. 68 (5), pp. e0150423. Date of Electronic Publication: 2024 Apr 08.
DOI:	10.1128/aac.01504-23
Abstrakt:	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. Competing Interests: H.C. is an employee of GSK and owns stock in GSK. T.P.D. and R.S. were employees of GSK at the time the study was conducted and may own stock in the company. M.A.-K. and K.A. are employees of ViiV Healthcare and own stock in GSK.
Databáze:	MEDLINE
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