Leichi Liu 1, Emmanuella C Osuala 2, Kelly E. Dooley 3, Kogieleum Naidoo 2,4, Paolo Denti 1, Anushka Naidoo 2,4, Roeland Wasmann 1
1 Division of Clinical Pharmacology, Department of Medicine, University of Cape Town (Cape Town, South Africa), 2 Centre for the AIDS Programme of Research in South Africa (CAPRISA), Nelson R Mandela School of Medicine, University of KwaZulu-Natal (Durban, South Africa), 3 Vanderbilt University Medical Center (Nashville, USA), 4 Centre for the AIDS Programme 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)
Introduction:
Bictegravir is an integrase strand transfer inhibitor (INSTI), and a key component of Biktarvy®, a fixed-dose combination containing 50 mg bictegravir alongside tenofovir alafenamide and emtricitabine [1]. Biktarvy® is widely recommended in resourced settings as a first-line initial combination antiretroviral therapy (ART) regimen for adults with HIV [2,3]. Because HIV infection increases the risk of developing tuberculosis (TB), co-infection remains a major clinical concern. In 2024, an estimated 1.23 million people died from TB globally, including approximately 150 000 people living with HIV—a population that accounts for about one-quarter of the total HIV-related deaths that year [4]. Better cotreatment options using potent, well tolerated antiretrovirals such as the INSTI’s are important in improving treatment outcomes and reducing mortality. As bictegravir is a substrate of CYP3A and UGT1A1, drugs such as rifampicin that induce these enzymes can significantly decrease bictegravir plasma concentrations. The efficacy and safety of bictegravir in individuals receiving rifampicin-based tuberculosis treatment were recently evaluated in the INSIGHT clinical trial. The geometric mean bictegravir AUC0-24h was found to be 62.4% lower during tuberculosis treatment compared with after completion of tuberculosis treatment despite doubling the dose (standard dose delivered twice-daily) [5].
Objectives:
The objective of this study was to develop a population pharmacokinetic (PopPK) model describing the impact of rifampicin co-administration on the pharmacokinetics of bictegravir among individuals with HIV-TB co-infection and to generate dosing recommendations to adjust for the reported drug-drug interaction.
Methods:
In INSIGHT (NCT04734652), adults with a CD4 count >50 cells/µL, who were either ART-naïve or had not been on ART for at least three months before enrolment were included. All participants had drug-sensitive tuberculosis and were enrolled within the first eight weeks of rifampicin-based first-line treatment initiation. Participants received twice-daily Biktarvy® (BIC/FTC/TAF 50/200/25 mg) co-administered with standard, weight-based oral TB treatment for the first 24 weeks. TB treatment consisted of an 8-week intensive phase with isoniazid, rifampicin, pyrazinamide, and ethambutol followed by a 16-week continuation phase with rifampicin and isoniazid. Twice-daily Biktarvy® was maintained for an additional two weeks following the completion of TB treatment. Participants were then switched to standard once-daily Biktarvy® until the end of the study (week 48).
Participants were assigned to either semi-intensive or sparse sampling. Semi-intensive sampling was done at weeks 4 and 12 (during TB treatment) at pre-dose, and 1, 2, 4, 6, and 8–12 hours post-dose, and at week 32 (after TB treatment) at pre-dose, and 1, 2, 4, 6–8, and 24-25 hours post-dose. Sparse sampling was done at pre-dose and 1–4 hours post-dose at week 4 and 12 (during TB treatment) and after TB treatment at week 32. Additionally, single pre-dose samples were obtained from all participants at week 8, 24, and 48. Plasma bictegravir concentrations were determined with a validated liquid chromatography-tandem mass spectrometry assay with a lower limit of quantification (LLOQ) of 0.01 mg/L [5]. Population pharmacokinetic analysis was performed using NONMEM version 7.5.1 [6].
Results:
We included 78 individuals and collected 1169 plasma samples. This included 732 semi-intensive, 210 sparse, and 227 pre-dose samples. Fourteen observations were below the LLOQ, all pre-dose samples. These visits were handled as a first dose rather than steady state observations.
A two-compartment model with lag time, first-order absorption, and first-order elimination best described the plasma concentration of bictegravir. Allometric scaling with fat-free mass (FFM) applied to all disposition parameters outperformed scaling with total body weight (dOFV= -17.57). For a typical individual with FFM of 49 kg, the parameter estimates (95%CI) were 2.06 (1.06, 3.06) h-1 for Ka, 0.205 (0.0048, 0.405) h for lag time, 0.666 (0.605, 0.727) L/h for apparent bictegravir clearance (CL/F), 8.98 (5.13, 12.8) L for apparent central volume of distribution (Vc/F). When co-administered with rifampicin, bictegravir clearance was increased 3.36 (2.88, 3.84) fold, and bioavailability decreased 31.7% (22.1%, 41.2%).
Conclusions:
The pharmacokinetic characteristics obtained in this study are comparable to previously published models from other populations [7]. In this South African cohort with HIV and TB, co-administration of rifampicin significantly altered bictegravir disposition, through threefold increased clearance, and a 34.9% decrease in bioavailability. This model will be used to support dose optimisation through further simulations.
References:
1. Gilead Sciences. Biktarvy. U.S. Food and Drug administration. https:// www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210251Orig1s000 MultidisciplineR.pdf
2. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV. Department of Health and Human Services. [Internet]. https://clinicalinfo.hiv.gov/sites/default/files/guidelines/documents/adult- adolescent-arv/guidelines-adult-adolescent-arv.pdf
3. European AIDS Clinical Society. European AIDS Clinical Society Guidelines Version 13.0. [Internet]. https://eacs.sanfordguide.com/en/eacs-hiv/art/eacs-initial-regimens-arv-naive-adults
4. World Health Organization (WHO). Global tuberculosis report 2025. Geneva; 2025.
5. Naidoo A, Naidoo K, Letsoalo MP, Wasmann RE, Dorse G, Perumal R, et al. Fixed-dose combination bictegravir–emtricitabine–tenofovir alafenamide twice-daily for treatment of HIV during rifampicin-based tuberculosis treatment (INSIGHT Study): a phase 2b, open-label, randomised non-comparative trial. Lancet HIV. 2026 Jan;13(1):e9–20.
6. ICON Development Solutions. NONMEM 7.5.1. Ellicott City, MD, USA
7. Ekobena P, Briki M, Dao K, Marzolini C, Andre P, Buclin T, et al. Population pharmacokinetics of bictegravir in real-world people with HIV. J Antimicrob Chemother. 2025 Oct;80(10):2782–9.
Reference: PAGE 34 (2026) Abstr 11944 [www.page-meeting.org/?abstract=11944]
Poster: Drug/Disease Modelling - Infection