(W-089) Modeling Lenacapavir (LEN) Exposure After Daily Oral Administration Alone and in Combination with Bictegravir (BIC) in People with HIV: A Population Pharmacokinetic Approach

Priyanka Arora, PhD – Senior Director, Clinical Pharmacologist, Gilead Sciences, Inc.; Dhananjay Marathe, PhD – Senior Director, Clinical Pharmacology, Gilead Sciences, Inc.; Ramesh Palaparthy, PhD – Executive Director and Head of Clinical Pharmacology, Gilead Sciences, Inc.; Ana Ruiz, PharmD, PhD – Head of Pharmacometrics, Gilead Sciences, Inc.; Nieves Velez de Mendizabal, PhD – Senior Director, Pharmacometrics. Clinical Pharmacology and Pharmacometrics, Gilead Sciences, Inc.

Objective: The objective is to develop a population pharmacokinetic (popPK) model of lenacapavir (LEN) to characterize its pharmacokinetics (PK) and identify significant covariates impacting LEN exposure. Model simulations were conducted to guide Phase 3 dose selection for the once-daily oral BIC/LEN fixed-dose combination (FDC) tablet formulation for the treatment of adult people with HIV-1 (PWH).

Methods: The popPK model was developed from a pooled dataset consisting of six studies in PWH and people without HIV, with LEN administered intravenously and orally as monotherapy and combined with BIC (co-formulated or co-administered). Selection of covariates to explain interindividual variability (IIV) in PK parameters involved graphical exploration between Empirical Bayes estimates and covariates, statistical significance (p-value < 0.001), relative standard error, and scientific or clinical relevance. Simulations based on existing adult weight distributions were conducted to evaluate LEN exposure prediction intervals from dosing scenarios of oral loading doses of 600 mg on Days 1 and 2, and a once daily maintenance dose of either 25 or 50 mg (tested in Phase 2 portion of ARTISTRY-1 study in PWH) to inform the Phase 3 dose. Percentage of participants predicted to be above the inhibitory quotient (IQ)-4 (IQ4) and IQ1 threshold values was calculated under aforementioned dose regimens.

Results: The structural model was adequately described by a 3-compartment model with linear elimination and a transit compartment model with an absorption lag in fed conditions for oral absorption. Baseline body weight effects on all clearance and volume of distribution terms were included, and allometric scaling was used with fixed exponents. Statistically significant covariate effects of dose on oral LEN bioavailability, fed state on oral absorption delay, and fasting/fed state on the oral transit compartment rate were included in the final model. When tested as a covariate, no significant interaction was identified between BIC given in combination with LEN at the explored doses. Simulated 90% prediction intervals of median concentrations following the specified dosing scenarios showed alignment with what was observed in the Phase 2 study. Higher concentrations of LEN exposures and percentage of participants above the IQ4 threshold for 50 mg was consistently higher than 25 mg across all time snapshots and missed dosing scenarios.

Conclusions: The developed LEN popPK model reasonably described the pharmacokinetics of LEN for 25 and 50 mg once daily maintenance dosing of LEN in combination with BIC in a Phase 2 study in PWH and reproduced the observed high IIV for LEN in population simulations. Simulation results suggested that LEN at 50 mg daily would provide better coverage for trough concentrations compared to 25 mg daily based on comparison between corresponding exposures and percentage of participants above the IQ4 and IQ1 thresholds at various time snapshots, including missed dose scenarios. These simulations supported the selection of 50 mg LEN in BIC/LEN FDC for the subsequent Phase 3 studies as this dose may offer better likelihood of sustaining continued robust HIV virologic suppression in the real-life scenario of any potential missed doses.

Citations: N/A