Émilie Pilote1,2, Nancy L Sheehan1,2, Amélie Marsot1
1Faculty of Pharmacy, University of Montreal, 2McGill University Health Center (MUHC)
Introduction: Dolutegravir (DTG) is a widely used integrase inhibitor for HIV treatment due to its efficacy and safety. It is recommended as a first- and second-line therapy across all populations [1]. DTG’s pharmacokinetics (PK) can be influenced by various factors, such as drug-drug interactions [2], body composition [3], and age [4]. Understanding these sources of variability is crucial to ensuring adequate drug exposure, given the potential effects of low or high concentrations. Therapeutic drug monitoring (TDM) can play a role in optimizing DTG therapy, particularly in individuals at risk of altered drug exposure. Population pharmacokinetic (PopPK) modeling offers a powerful tool for characterizing DTG disposition across diverse patient groups—including adults, pediatrics, and pregnant individuals—helping to refine dosing strategies and optimize treatment outcomes. Objective: This narrative review synthesizes existing DTG PopPK models, highlighting key PK parameters and covariate effects. Methods: A literature search of published PopPK studies on DTG was conducted in Embase [5] and Medline [6] (inception to January 13, 2025) using keywords related to ‘PopPK’, ‘Non-linear mixed effect’, and ‘dolutegravir’. Studies were included if they were on the development or revision of a human plasma DTG PopPK model but excluded if details were insufficient. Data on study design, populations, PopPK models, covariates, and simulations were extracted. Results: Among the 93 identified studies, 16 (published between 2015 and 2024) were eligible: 11 in adults, 3 in pediatrics (including one with two models), and 2 in pregnancy. Adult studies [7-17] employed one- (n=7) or two-compartment (n=4) models, with some incorporating transit compartments (n=3) or lag times (n=6) to describe a delay in absorption. Pediatric studies [18-20] included children of all ages, except for one that was restricted to adolescents (12-18 years); and one-compartment models predominated (n=3). Pregnancy studies [21,22] developed both maternal and infant models. A model for pregnant women (two-compartment for plasma) also incorporated compartments for the fetus (umbilical cord) and breast milk. This study also developed a one-compartment infant model described by an elimination rate constant (ke) and a transfer rate constant from breast milk to infant. The other model developed for pregnant women was a one-compartment model, with a one-compartment model for infants described by an estimated ke only. Estimated PK parameters varied across populations. Clearance (CL) ranged from 0.713 to 2.82 L/h in adults, from 0.722 to 1.03 L/h in pediatrics, and was 0.730 and 1.50 L/h in pregnant individuals. The total volume of distribution (Vd) ranged from 12.4 to 20.2 L in adults, from 8.66 to 16.6 L in pediatrics, and was 18.5 and 26.6 L in pregnant individuals. The absorption rate constant (ka) ranged from 1.41 to 2.24 h?¹ in adults, from 0.504 to 1.74 h?¹ in pediatrics, and was 0.750 and 1.08 h?¹ in pregnant individuals. Infant ke was estimated at 0.0157 and 0.0162 h?¹. To account for body size, most adult and pediatric models included body weight or fat-free mass as covariates on all clearance and volume parameters. In adults, the covariates mostly influencing CL were the concomitant use of DTG inducers or inhibitors, smoking, and total bilirubin levels. Significant covariates in pediatric studies were total bilirubin, ethnicity, age, DTG formulation, food intake, and background antiretrovirals. In maternal models, one study incorporated pregnancy and body weight as covariates. Conclusions: This review consolidates DTG PopPK knowledge across populations, elucidating key PK parameters and covariates influencing DTG exposure. However, no PopPK models were identified for elderly and obese individuals, thus indicating a need for PopPK studies in these vulnerable populations, especially since people living with HIV are growing older with the advancements made in HIV treatments [23].
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Population pharmacokinetics of unbound and total dolutegravir concentrations in children aged 12 years and older: a PK substudy of the SMILE trial. J Antimicrob Chemother. 2023;78(4):1041-9. [19] Chandasana H, Thapar M, Hayes S, Baker M, Gibb DM, Turkova A, et al. Population Pharmacokinetic Modeling of Dolutegravir to Optimize Pediatric Dosing in HIV-1-Infected Infants, Children, and Adolescents. Clin Pharmacokinet. 2023;62(10):1445-59. [20] Waalewijn H, Wasmann RE, Bamford A, Gibb DM, McIlleron HM, Colbers A, et al. Population Pharmacokinetics of Dolutegravir in African Children: Results From the CHAPAS-4 Trial. J Pediatric Infect Dis Soc. 2024;13(9):496-500. [21] Dickinson L, Walimbwa S, Singh Y, Kaboggoza J, Kintu K, Sihlangu M, et al. Infant Exposure to Dolutegravir Through Placental and Breast Milk Transfer: A Population Pharmacokinetic Analysis of DolPHIN-1. Clin Infect Dis. 2021;73(5):e1200-e7. [22] Piscitelli J, Nikanjam M, Best BM, Acosta E, Mirochnick M, Clarke DF, et al. 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Reference: PAGE 33 (2025) Abstr 11632 [www.page-meeting.org/?abstract=11632]
Poster: Drug/Disease Modelling - Infection