Marjorie Z. Imperial, Emma A. Hughes, Vamshi Jogiraju, Naveed Shaik, Renu Singh, Nieves Velez de Mendizabal
Clinical Pharmacology Department, Gilead Sciences Inc.
Introduction: Lenacapavir (LEN) is a novel long-acting, first-in-class, selective inhibitor of HIV-1 capsid function, currently approved for multidrug resistant HIV-1 infection in heavily treatment experienced people with HIV [1,2]. Following subcutaneous (SC) administration, LEN is absorbed gradually over several months, with a time to maximal concentration of 77-84 days and an apparent half-life of 8-12 weeks. The absorption of LEN is complex and involves multiple parallel phases. This complexity makes characterization of LEN absorption and identifying covariates challenging yet crucial to understand LEN’s PK properties.
Objectives: Characterize absorption and disposition of LEN after IV and SC administration in healthy participants using a step-wise modeling approach.
Methods: This analysis included pooled LEN plasma concentrations from two phase 1 studies in healthy participants. Briefly, the dataset included a total of 42 participants and 1045 concentrations of which 18 individuals received a single IV dose of LEN (10 mg or 20 mg) and 24 received SC abdominal injection(s) as a single dose (309 mg or 927 mg). To ensure characterization of the absorption and disposition of LEN, given its fast distribution and elimination compared to slower and complex absorption processes, a stepwise modeling approach was implemented. Initially, data from the IV study with single doses was used to develop an IV PK model to characterize the systemic disposition (distribution and elimination) of LEN by optimizing structural and random effect models and identifying covariates. Secondly, using the IV PK model as the foundation to describe the systemic disposition of LEN, an IV-SC PK model was developed to characterize the SC absorption of LEN by optimizing structural and random effect models and identifying covariates. Weight, age, body mass index, sex, race, and baseline glomerular filtration rate were evaluated as covariates on clearance, volume of distribution and absorption parameters. Inclusion of covariates were based on visual inspection of the data, improvement in model fit, and scientific and clinical relevance. NONMEM version 7.5 was used to develop the population PK (PopPK) models.
Results: LEN disposition following IV administration was adequately described by a 3-compartment model with linear elimination. Following SC administration of LEN, absorption was adequately described by three parallel transit compartment absorption phases. An initial absorption phase occurs rapidly (completed within the first day) without a lag time, while the second and third absorption phases have delays described by lag times of 10.7 and 37.3 days, respectively. Together these three phases led to a median observed time to reach maximum concentration of 84 days (range 35 to 168 days). SC bioavailability was estimated as 83.7% over the duration of sampling, with 4.0% of the bioavailable dose accounted for in the initial absorption phase, 41.0% in the the second absorption phase, and 55.0% in the third absorption phase. Inter-individual variability was estimated for all three absorption rates as well as both lag times. Clearance and volume of distribution terms were allometrically scaled. Given the homogeneity of the population in this analysis (healthy participants), no additional covariates were visually or significantly identified at this stage.
Conclusions: A stepwise modeling approach was implemented to characterize the complex absorption and disposition of LEN. The modeling strategies and framework used in this analysis are valuable tools that can be used to describe the disposition and absorption of LEN across different routes of administration and inform regimen selection for LEN.
References:
[1] SUNLENCA United States Prescribing Information (2022). Package insert. Foster City,
CA: Gilead Sciences Inc. URL: https://www.accessdata.fda.gov/drugsatfda_docs/label/
2022/215973s000lbl.pdf.
[2] SUNLENCA EU Summary of Product Characteristics (2022). County Cork, Ireland: Gilead Sciences Inc. URL: https://www.ema.europa.eu/en/medicines/human/EPAR/sunlenca.
Reference: PAGE 32 (2024) Abstr 11073 [www.page-meeting.org/?abstract=11073]
Poster: Drug/Disease Modelling - Infection