Population pharmacokinetic modeling of dolutegravir/lamivudine to support a once-daily fixed-dose combination regimen in virologically suppressed adults living with HIV-1.
Antimicrob Agents Chemother
; 68(5): e0150423, 2024 May 02.
Article
en En
| MEDLINE
| ID: mdl-38587380
ABSTRACT
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.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Oxazinas
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Piperazinas
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Piridonas
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Infecciones por VIH
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VIH-1
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Lamivudine
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Fármacos Anti-VIH
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Compuestos Heterocíclicos con 3 Anillos
Límite:
Adult
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Año:
2024
Tipo del documento:
Article