Baralee Punyawudho 1, Anan Chanruang 1, Angela K Birnbaum 3, Silvia Illamola 3, Sasithorn Sirilun 4, Suthunya Chupradit 1, Sasiwimol Ubolyam 2, Napon Hiranburana 2, Yong Soon Cho 4, Jae Gook Shin 4, Anchalee Avihingsanon 2
1 Department Of Pharmaceutical Care, Faculty Of Pharmacy, Chiang Mai University (, Thailand), 2 HIV-NAT, Thai Red Cross AIDS Research and Infectious Diseases Centre (Bangkok, Thailand), 3 Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota (Minneapolis, USA), 4 Department of Pharmaceutical Sciences, Faculty of Pharmacy, Chiang Mai University (, Thailand), 5 Center for Personalized Precision Medicine of Tuberculosis, Inje University College of Medicine (Busan , Republic of Korea)
Objectives: Dolutegravir (DTG), a second-generation integrase strand transfer inhibitor, is currently recommended as a first-line treatment for people living with HIV (PLWH). However, its pharmacokinetics exhibit significant inter-individual variability (IIV) [1-2], which is driven by both non-genetic factors such as sex, age, body weight, and total bilirubin, and genetic polymorphisms, specifically in UGT1A1, ABCG2, and NR1I2 [3-4]. Ultimately, these variations may influence both the clinical efficacy and safety profiles of DTG treatment. This study aimed to characterize the population pharmacokinetics (popPK) of DTG in Thai PLWH and to evaluate the impact of relevant covariates on its pharmacokinetic parameters.
Methods: This cross-sectional analysis was conducted in Thai PLWH at the HIV Netherlands Australia Thailand Collaboration (HIV-NAT), Thai Red Cross AIDS and Infectious Diseases Research Centre in Bangkok, Thailand. Data were pooled from two pharmacokinetic sub-studies of DTG (ClinicalTrials.gov identifiers: NCT03785106 and NCT03727152). Intensive blood samples were collected at pre-dose and 1, 2, 4, 6, 8, 10, 12, and 24 hours post-dose. The popPK model was developed using NONMEM®, and the final model was subsequently utilized to determine the optimal DTG dosage for this population via Monte Carlo simulations. The probability of target attainment (PTA) for various dosing regimens was assessed based on the percentage of simulated individuals achieving pre-defined efficacy targets (IC90 > 0.064 mg/L and EC90 > 0.3 mg/L) [5]. Furthermore, the percentage of simulated individuals with concentrations over the Neuropsychiatric Adverse Events (NP-AEs) cut points was also determined.
Results: Data from 221 PLWH, comprising 1,122 DTG plasma concentrations, were included in the popPK analysis. DTG pharmacokinetics were best characterized by a one-compartment model with first-order absorption with lag time and first-order elimination. Notably, the combination of the UGT1A1 poor metabolizer status and the NR1I2 63396 TT genotype was identified as a significant covariate, resulting in a 30% reduction in DTG apparent clearance (CL/F). Simulation results demonstrated that a 50 mg QD regimen maintained trough concentrations above both IC90 and EC90 more than 95% of individuals across all cohorts. Nonetheless, a substantial proportion (59%–88%) of PLWH exhibited DTG trough concentrations exceeding the NP-AE safety threshold. Consequently, a dose reduction to 25 mg QD was evaluated for optimization. This reduced regimen maintained high target attainment rates for IC90 (>90%) and EC90 (>80%), with the exception of the high-weight wild-type group. Notably, the proportion of individuals exceeding the NP-AE threshold decreased to below 20% for all wild type individuals, regardless of weight and the high-weight variant-type group. However, 40% of the low-weight variant-type group remained above the threshold.
Conclusions: A reduced dose of DTG 25 mg QD may be appropriate for Thai PLWH, particularly those with low body weight carrying the UGT1A1 poor metabolizer and NR1I2 63396 TT genotypes to mitigate the risk of NP-AEs frequently observed in clinical practice.
References:
1. Menard A, Montagnac C, Solas C, Meddeb L, Dhiver C, Tomei C, et al. Neuropsychiatric adverse effects on dolutegravir: an emerging concern in Europe. AIDS. 2017;31(8).
2. Povar-Echeverría M, Comet-Bernad M, Gasso-Sánchez A, Ger-Buil A, Navarro-Aznarez H, Martínez-Álvarez R, et al. Neuropsychiatric adverse effects of dolutegravir in real-life clinical practice. Enfermedades Infecciosas y Microbiología Clínica (English Edition). 2021;39(2):78-82.
3. Elliot ER, Neary M, Else L, Khoo S, Moyle G, Carr DF, et al. Genetic influence of ABCG2, UGT1A1 and NR1I2 on dolutegravir plasma pharmacokinetics. Journal of Antimicrobial Chemotherapy. 2020;75(5):1259-66.
4. Yagura H, Watanabe D, Kushida H, Tomishima K, Togami H, Hirano A, et al. Impact of UGT1A1 gene polymorphisms on plasma dolutegravir trough concentrations and neuropsychiatric adverse events in Japanese individuals infected with HIV-1. BMC Infectious Diseases. 2017;17(1):622.
5. van Lunzen J, Maggiolo F, Arribas JR, Rakhmanova A, Yeni P, Young B, et al. Once daily dolutegravir (S/GSK1349572) in combination therapy in antiretroviral-naive adults with HIV: planned interim 48 week results from SPRING-1, a dose-ranging, randomised, phase 2b trial. The Lancet Infectious Diseases. 2012;12(2):111-8.
Reference: PAGE 34 (2026) Abstr 12061 [www.page-meeting.org/?abstract=12061]
Poster: Clinical Applications