Population Plasma and Urine Pharmacokinetic Data and Modelling of Casdatifan Supports Administration to Participants with Moderate Renal Impairment
Authors: Ghasemi Mohammad , Liao Ken , Paterson Elaine , Foster Paul , Jin Lixia , Agoram Balaji 
Published: February 2025

Objectives: Casdatifan (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 plasma and urine PK model describing the relationship between dose and casdatifan PK, conduct simulations to compare the exposure between subjects with normal renal function and those with moderate renal impairment, and support inclusion of moderate renally impaired patients in future clinical trials.METHODS: Casdatifan plasma concentrations were obtained from 55 healthy participants in a Phase 1 study, ARC-14 (NCT05117554). The available plasma PK data included a casdatifan dose range of 3 to 100 mg single oral dose, and multiple oral doses of casdatifan from 15 mg daily to 50 mg daily. Casdatifan urine PK data (in terms of the cumulative urine excreted unchanged casdatifan) were collected from 25 participants across single dose of 100 mg (from predose to 144 h post dose) and at multiple oral doses of 15 to 50 mg daily (predose to 24 h post dose at Day 1 and Day 7). Population plasma and urine PK modeling was conducted using mixed effects methodology with NONMEM, v7.5.RESULTS: Casdatifan showed favorable PK profiles with a dose-proportional increase in exposure in the dose range tested (3-100 mg) and an apparently half-life of approximately 21 h. Casdatifan renal clearance ranged from 21.8 to 25.2 mL/min at dose levels of 15-100 mg and was comparable across all dose levels, accounting for approximately 30% of total systemic clearance of casdatifan.A two-compartment model with first-order absorption adequately described the casdatifan plasma PK across the dose range tested. A multi-compartment model including a urine compartment was chosen to describe both the plasma and urine data with between‐subject variability on apparent non-renal clearance, renal clearance, apparent volume of distribution, and absorption rate constant. Body weight and creatinine clearance were found to be statistically significant covariates on apparent volume of distribution and on renal clearance, respectively.Model simulations indicated that the overall difference in geometric means of PK parameters (steady-state peak and average concentrations) between participants with normal and moderate impairment renal function were approximately 20% across all dose levels and within the range of casdatifan PK variability. Therefore, this predicted small increase in exposure in patients with moderate renal impairment is expected to be clinically insignificant, thus supporting inclusion of these patients in casdatifan studies to allow a broader patient population to have access to this novel therapeutic candidate.CONCLUSION: A preliminary population plasma and urine PK model was developed to adequately describe casdatifan plasma and urine PK profile. The model supports inclusion of moderate renal impaired patients in casdatifan studies.Citations: 1