Ruben van de Venter 1, Paolo Denti 1, Sean Wasserman 2,3, Linda Harrison 4, Ashley McKhann 4, Elisa Ignatius 5, Gary Maartens 1, Susan Swindells 6, Anushka Naidoo 7, Justin Shenje 8, Anchalee Avihingsanon 9, Richard Chaisson 5, Roeland Wasmann 1
1 Division of Clinical Pharmacology, Department of Medicine, University of Cape Town (Cape Town, South Africa), 2 Wellcome Discovery Research Platforms in Infection, Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town (Cape Town, South Africa), 3 Institute for Infection and Immunity, City St George’s, University of London (London, United Kingdom), 4 Center for Biostatistics in AIDS Research, Harvard TH Chan School of Public Health (Boston, United States of America), 5 Divisions of Clinical Pharmacology and Infectious Diseases, Johns Hopkins University School of Medicine (Baltimore, United States of America), 6 Division of Infectious Diseases, Department of Internal Medicine, University of Nebraska Medical Center (Omaha, United States of America), 7 Center for the AIDS Program of Research in South Africa (CAPRISA), South African Medical Research Council (SAMRC)-CAPRISA-TB-HIV Pathogenesis and Treatment Research Unit Nelson R Mandela School of Medicine, University of KwaZulu-Natal (Durban, South Africa), 8 South African Tuberculosis Vaccine Initiative, University of Cape Town (Cape Town, South Africa), 9 HIVNAT, Thai Red Cross AIDS and Infectious Diseases Research centre and Center of Excellence in Tuberculosis, Faculty of Medicine, Chulalongkorn University (Bangkok, Thailand)
Objectives:
Dolutegravir remains a key component of first-line antiretroviral therapy in settings with a high burden of HIV and tuberculosis (TB) [1]. Rifapentine forms part of a newer, shortened four-month TB regimen and is a potent inducer of the hepatic drug-metabolising enzymes UGT1A1 and CYP3A4, raising concern for dolutegravir underexposure during co-administration [2–4]. In this study, dolutegravir dosing was increased to 50 mg twice daily to maintain therapeutic concentrations associated with virological suppression. The objective was to characterise dolutegravir pharmacokinetics when co-administered with rifapentine, using population pharmacokinetic modelling, and to evaluate alternative dosing strategies through model-based simulations.
Methods:
We conducted a phase II, open-label, single-arm pharmacokinetic study in South Africa and Thailand. Adults with HIV-associated TB received an 8-week intensive phase with daily rifapentine (1200 mg), moxifloxacin (400 mg), isoniazid (300 mg), and pyrazinamide (25–35 mg/kg), followed by a 8-week continuation phase with daily rifapentine, moxifloxacin, and isoniazid at the same doses. Twice daily dolutegravir (50 mg) was initiated at week 6 and transitioned to once daily two weeks after TB treatment completion. Intensive pharmacokinetic sampling was performed 2 weeks after initiating twice daily dolutegravir and 2 weeks after transitioning to once daily dolutegravir (pre-dose, 1, 2, 4, 6, 8–10, and 24h post-dose). Dolutegravir concentrations were quantified at the University of Cape Town laboratory by LC–MS/MS, with a lower limit of quantification (LLOQ) of 0.03 µg/mL.
One- and two-compartment disposition models with first-order absorption were evaluated using FOCE+I, with alternative absorption models incorporating a lag time and/or zero-order input, or transit compartments. The effects of body weight and fat-free mass were assessed through allometric scaling of disposition parameters. Covariates tested included rifapentine effects on clearance, bioavailability, and absorption.
The final model was used with uncertainty in parameter estimates to simulate (n=1000) the probability of achieving dolutegravir Ctrough above efficacy thresholds under four dosing scenarios: 50 mg once daily without rifapentine (standard regimen), and with rifapentine 50 mg once daily, 50 mg twice daily, and 100 mg once daily. The efficacy thresholds tested were 0.158 µg/mL (the SPRING-1 10 mg once-daily 5th percentile Ctrough with virological suppression equivalent to standard dosing) [5], and 0.064 µg/mL (the protein-adjusted 90% inhibitory concentration, PA-IC90) [1].
Results:
The cohort included 28 antiretroviral-naïve adults (54% male), predominantly black (93%), with a median (IQR) weight of 56.7 kg (49.2–60.7) and age of 36 years (31–39). A total of 347 samples were available for analysis, with no concentrations below the LLOQ.
The data were best described by a one-compartment model with first-order elimination and transit-compartment absorption. Allometric scaling by fat-free mass improved model fit compared to total body weight (ΔOFV = -5.77 vs -3.72). For a typical participant with a fat-free mass of 40 kg, the estimated clearance was 1.00 L/h (95% CI, 0.85–1.19). Rifapentine co-administration increased dolutegravir clearance 2.18-fold (95% CI, 1.90–2.54; ΔOFV = –47.8) and reduced bioavailability by 24.7% (95% CI, 10.6–37.1; ΔOFV = -9.25).
Model-based simulations predicted that dolutegravir 50 mg once daily, in the absence of rifapentine, maintained concentrations above 0.158 µg/mL in 98.0% (95% CI, 92.6–99.9) of individuals and above 0.064 µg/mL in 99.9% (95% CI, 98.2–100). Co-administration with rifapentine predicted that <30% would remain above 0.158 µg/mL and <70% above 0.064 µg/mL. Increasing dolutegravir dosing to 50 mg twice daily was predicted to maintain 98.8% (95% CI, 94.0–100) above 0.158 µg/mL and 99.9% (95% CI , 98.9–100) above 0.064 µg/mL, while 100 mg once daily was predicted to maintain concentrations above these thresholds in 58.8% (95% CI , 41.9–78.5) and 85.2% (95% CI , 71.3–97.2) of individuals, respectively. Conclusion: Rifapentine reduced dolutegravir exposure by increasing clearance and decreasing bioavailability, rendering standard once-daily dosing insufficient to maintain concentrations above current efficacy targets. Twice-daily dolutegravir dosing mitigates this interaction and maintains target attainment, whereas 100 mg once daily does not consistently meet the SPRING-1–derived threshold. These findings support twice-daily dolutegravir during rifapentine-containing shortened TB regimens, while further work to refine efficacy targets may enable simpler dosing strategies and improved adherence. References: 1 Cottrell ML, Hadzic T, Kashuba ADM. Clinical pharmacokinetic, pharmacodynamic and drug-interaction profile of the integrase inhibitor dolutegravir. Clin Pharmacokinet. 2013 Nov;52(11):981–94. 2 Maartens G, Boffito M, Flexner CW. Compatibility of next-generation first-line antiretrovirals with rifampicin-based antituberculosis therapy in resource limited settings. Curr Opin HIV AIDS. 2017 Jul;12(4):355–8. 3 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 Infect Dis. 2017 Sep;17(1). 4 Reese MJ, Savina PM, Generaux GT, Tracey H, Humphreys JE, Kanaoka E, et al. In vitro investigations into the roles of drug transporters and metabolizing enzymes in the disposition and drug interactions of dolutegravir, a HIV integrase inhibitor. Drug Metabolism and Disposition. 2013 Feb;41(2):353–61. 5 Weld ED, Beattie T, Moodley J, Mapendere M, Salles I, Solans BP, et al. Simultaneous initiation of dolutegravir-based antiretroviral therapy and once-weekly rifapentine and isoniazid for tuberculosis prevention in antiretroviral-naive people with HIV: an open-label, non-randomised, phase 1/2 trial. Lancet HIV. 2025 Jun;12(6):e428–39.
Reference: PAGE 34 (2026) Abstr 12158 [www.page-meeting.org/?abstract=12158]
Poster: Drug/Disease Modelling - Infection