Population Pharmacokinetic Modeling of Plasma and Intracellular Bictegravir in People Living With HIV

BACKGROUND: The first-line second-generation HIV integrase inhibitor bictegravir is widely used, but interindividual variability in response persists. Its plasma pharmacokinetics have been described, but intracellular exposure in peripheral blood mononuclear cells (PBMCs) is poorly characterized. This study aimed to develop a bictegravir population pharmacokinetic model linking plasma and PBMC concentrations to quantify intracellular exposure variability and support exposure-response analyses. METHODS: This secondary analysis used prospectively collected plasma and PBMC concentrations from bictegravir-treated people living with HIV. Plasma concentrations were linked to intracellular PBMC exposure using population pharmacokinetic modeling. Candidate demographic and pharmacogenetic covariates were considered, and simulations assessed how plasma-PBMC variability influences intracellular exposure. RESULTS: Data from 51 participants yielded 138 plasma and 42 PBMC concentrations. The PBMC concentrations were linked to plasma concentrations described by a 1-compartment model, yielding a steady-state intracellular-plasma concentration ratio of 0.038, with high interindividual variability (89% CV). No covariates were retained in the final model. All model-adjusted steady-state plasma trough concentrations exceeded the reference threshold (760 ng/mL), whereas 7% of the PBMC concentrations fell below the corresponding model-derived intracellular threshold (29 ng/mL). Simulations showed that the probability of the cellular concentration falling below this exploratory intracellular threshold was 50% at 760 ng/mL and decreased with increasing plasma trough concentrations. CONCLUSIONS: This study provides the first model-based link between bictegravir plasma and PBMC concentrations using real-world therapeutic drug monitoring data, showing high variability in the plasma-intracellular relationship. The developed framework supports future intracellular exposure-response analyses.