Population Pharmacokinetic and Pharmacodynamic Analyses of Cedirogant in Healthy Subjects and Subjects with Moderate to Severe Psoriasis
JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY(2023)
Abstract
Cedirogant is a small molecule inverse agonist of retinoic acid related orphan receptor gamma, thymus (RORγt), with expected effects of attenuating the IL-23/IL-17 pathway implicated in the etiology of psoriasis (PsO). Data from two Phase 1 studies were utilized in a population pharmacokinetic and pharmacodynamic modeling approach to characterize cedirogant pharmacokinetics and target engagement dynamics with ex-vivo IL-17A across doses ranged from 20 mg to 750 mg following single and multiple doses. Pharmacokinetics of cedirogant were best described by a two-compartment pharmacokinetic model with delayed absorption and an enzyme turnover compartment. Cedirogant model-estimated steady-state average concentration during a dosing interval and maximum plasma concentrations were (median [5th, 95th percentiles]) 7.56 μg/mL [4.45, 11.9 μg/mL] and 11.8 μg/mL [9.56, 17.5 μg/mL], respectively, for participants with PsO with 375 mg once-daily regimen. Cedirogant apparent oral clearance and apparent steady-state volume of distribution were estimated to be 24.5 L/day and 46.3 L, respectively. The exposure-response relationship between cedirogant exposure and ex- vivo IL-17A inhibition was adequately characterized by a direct, saturable inhibition model without temporal delay. The model-estimated half maximal inhibition concentration (IC50) and maximum extent of inhibition (Imax) from baseline values were 0.56 μg/mL and 76%, respectively. The model-predicted maximum percentage of ex-vivo IL17A inhibition from baseline ranged from 64% for 75 mg QD to 73% approaching Imax for 375 mg QD dose. The established relationship between cedirogant exposure and biomarker effect served as the basis for dose selection for the Phase 2 dose-ranging study for cedirogant in psoriasis.
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Key words
psoriasis,cedirogant,population pharmacokinetic,pharmacodynamic analyses
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