Director, Clinical Pharmacology Arcus Biosciences Cheektowaga, New York, United States
Background: AB521, an orally bioavailable small-molecule inhibitor of HIF-2α, potently inhibits transcription of HIF-2α-dependent genes in cell lines and preclinical species. The objective of this analysis was to develop a population PK model describing the relationship between dose and AB521 PK, identify influential covariates of AB521 PK, and support dose selection in future clinical trials. Methods: AB521 plasma concentrations were obtained from 55 healthy participants in an ongoing Phase 1 studies, ARC-14 (NCT05117554). The available PK data included an AB521 dose range of 3 to 100 mg single oral dose and multiple oral doses of AB521 from 15 mg daily to 50 mg daily. Covariates such as body weight, age, body mass index, creatinine clearance, alanine transaminase, albumin, and total bilirubin were evaluated. Population PK modeling was conducted using mixed effects methodology with NONMEM, v7.5. Results: A one-compartment model with first-order absorption and between‐subject variability on apparent clearance, apparent volume of distribution, and absorption rate constant adequately described the AB521 plasma PK across the dose range tested in all participants. The half-life for AB521 estimated by population PK modeling is 20.7 h. Model simulations indicated that AB521 exposure following administration of daily doses ≥30 mg achieved a pre‐set effective exposure threshold in the majority of patients. Based on the simulations and preliminary safety information, multiple dose levels were identified for expansion cohorts in ARC-20 to enable exploration of the full therapeutic potential of HIF-2α inhibition. Conclusion: A preliminary population PK model was developed to adequately describe AB521 plasma PK profile. The model supports selection of the appropriate dose range for expansion.
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