Population pharmacokinetic modeling of oral brepocitinib in healthy volunteers and patients with immuno‐inflammatory diseases

Abstract

The objective of this population pharmacokinetic (PK) analysis was to characterize the concentration–time profile of brepocitinib plasma concentration after single‐ and multiple‐oral administration in healthy volunteers (HVs) and patients with immuno‐inflammatory diseases. Blood samples from phase I HV and phase II clinical studies of patients with alopecia areata, psoriasis, psoriatic arthritis, ulcerative colitis (UC), vitiligo, and hidradenitis suppurativa were analyzed using a nonlinear mixed‐effects modeling approach. Effects of patients' characteristics on brepocitinib exposure were investigated. Overall, 8552 brepocitinib plasma concentrations from 775 individuals were included in the analysis. The PKs of brepocitinib were adequately described by a two‐compartment model with first‐order absorption and a lag time for tablet formulation, dose‐dependent bioavailability, and Box–Cox transformed interindividual variabilities on apparent clearance (CL/F) and apparent central volume of distribution (Vc/F). For a typical 70‐kg non‐Asian female patient with baseline aspartate aminotransferase of 22 unit/liter, CL/F and Vc/F estimates were 17.5 L/h and 88.5 L, respectively. Asians had a higher exposure (independent of body weight), caused by a 10% lower CL/F when compared to other individuals. Independent of baseline body weight, the male population showed 13% higher Vc/F compared to the female population. Patients with UC were predicted to have 46% slower absorption rate compared to other individuals. The PKs of brepocitinib were well‐characterized by a two‐compartment model with first‐order absorption and dose‐dependent bioavailability. Several covariates, such as race and sex, were identified to have statistically significant, but not clinically meaningful, effects on the estimated PK parameters.

Therapeutic Potential of Targeting the JAK/STAT Pathway in Psoriasis: Focus on TYK2 Inhibition

“…This selective inhibition leads to the modulation of multiple cytokine pathways involved in the pathogenesis of several diseases. Specifically, brepocitinib has been proposed for the treatment of systemic lupus erythematosus, Crohn’s disease, ulcerative colitis (UC), alopecia areata (AA), vitiligo, and hidradenitis suppurativa (HS) [ 79 , 80 , 81 ]. Also, topical administration of this small molecule had been developed for atopic dermatitis [ 79 ].…”

“…Specifically, brepocitinib has been proposed for the treatment of systemic lupus erythematosus, Crohn’s disease, ulcerative colitis (UC), alopecia areata (AA), vitiligo, and hidradenitis suppurativa (HS) [ 79 , 80 , 81 ]. Also, topical administration of this small molecule had been developed for atopic dermatitis [ 79 ]. Currently, brepocitinib is under development for psoriatic disorders [ 82 ].…”