Cedirogant Population Pharmacokinetics and Pharmacodynamic Analyses of Interleukin‐17A Inhibition in Two Phase I Studies in Healthy Participants and Participants with Moderate to Severe Psoriasis

Abstract

AbstractCedirogant (ABBV‐157) is an orally bioavailable inverse agonist of retinoic acid‐related orphan receptor gamma thymus. Data from 2 Phase 1 studies were used to characterize cedirogant pharmacokinetics and evaluate target engagement. Cedirogant plasma concentrations and ex vivo interleukin 17A (IL‐17A) concentrations from healthy participants and participants with moderate to severe psoriasis (PsO) were analyzed in a population pharmacokinetic and pharmacodynamic modeling framework to characterize cedirogant pharmacokinetics following single and multiple doses and assess ex vivo IL‐17A inhibition in relation to cedirogant exposure. Cedirogant population pharmacokinetics were best described by a 2‐compartment pharmacokinetic model with delayed absorption and an enzyme turnover compartment to describe cytochrome P450 3A autoinduction. The pharmacokinetics of cedirogant were comparable between healthy participants and participants with PsO. Cedirogant steady‐state average and maximum plasma concentrations were predicted to be 7.56 and 11.8 mg/L, respectively, for participants with PsO for the 375 mg once‐daily regimen on Day 14. The apparent clearance and apparent volume of distribution for cedirogant were estimated to be 24.5 L/day and 28.2 L, respectively. A direct maximum inhibition model adequately characterized the exposure‐response relationship of cedirogant and ex vivo IL‐17A inhibition, indicating no temporal delay between exposure and response with a saturable inhibition of IL‐17A. Model‐estimated half‐maximal inhibitory concentration and maximum inhibition values for cedirogant inhibition of ex vivo IL‐17A were 0.56 mg/L and 0.76, respectively. The established relationship between cedirogant exposure and biomarker effect supported dose selection for the Phase 2 dose‐ranging study in patients with PsO.