Pharmacokinetics and Safety of the Tyrosine Kinase2 Inhibitor Deucravacitinib in Healthy Chinese Subjects.

Abstract

Deucravacitinib, an oral, selective, allosteric tyrosine kinase2 inhibitor, blocks cytokine signaling involved in psoriasis pathogenesis. This ethnic-bridging study evaluated deucravacitinib pharmacokinetics, tolerability, and safety in healthy Chinese subjects. This phaseI, double-blind, single-/multiple-dose study randomized healthy Chinese subjects 4:1 to a single dose of deucravacitinib 6mg or placebo (group1) or deucravacitinib 12mg or placebo (group2) on day1; groups1 and 2 received deucravacitinib 6mg and 12mg once daily, respectively, or placebo on days5-19. Blood samples were collected on days1-5 (0 predose-96h postdose), day5 (0-24h postdose), days9 and 12 (0h), and day19 (0-24h postdose). Deucravacitinib and metabolite (BMT-153261, BMT-158170) concentrations were determined using liquid chromatography/mass spectrometry; pharmacokinetic parameters were calculated using noncompartmental analysis. Urine was collected on days1-4 (4h predose-96h postdose). Safety was monitored throughout. Forty healthy Chinese subjects (groups1 and 2: deucravacitinib, n = 32; placebo, n = 8) were enrolled. Deucravacitinib was rapidly absorbed after single-/multiple-dose administration, with median time to maximal plasma concentration of 1.5-2.3 h. Systemic exposure after single or multiple doses increased approximately twofold with twofold dose increase. Modest deucravacitinib accumulation was observed after multiple-dose administration (1.3- to 1.4-fold increase in area under the curve [AUC] under one dosing interval). Metabolite-to-parent ratios for maximal plasma concentration and AUC remained consistent in each dose group. Mean urinary percent recovery and renal clearance were similar between dose groups. Most adverse events (AEs) were mild/moderate, with no serious treatment-related AEs, deaths, or discontinuations due to AEs. Deucravacitinib was safe and well tolerated in healthy Chinese subjects. Deucravacitinib exhibited rapid absorption, dose-related increases in exposure, comparable half-life, and no evidence of time-dependent pharmacokinetics, suggesting minimal effect of Chinese ethnicity on deucravacitinib pharmacokinetics. NCT03956953.