Pharmacokinetics and Safety of the Tyrosine Kinase 2 Inhibitor Deucravacitinib in Healthy Chinese Subjects.

Introduction: Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, blocks cytokine signaling involved in psoriasis pathogenesis. This ethnic-bridging study evaluated deucravacitinib pharmacokinetics, tolerability, and safety in healthy Chinese subjects. Methods: This phase I, double-blind, single-/multiple-dose study randomized healthy Chinese subjects 4:1 to a single dose of deucravacitinib 6 mg or placebo (group 1) or deucravacitinib 12 mg or placebo (group 2) on day 1; groups 1 and 2 received deucravacitinib 6 mg and 12 mg once daily, respectively, or placebo on days 5–19. Blood samples were collected on days 1–5 (0 predose–96 h postdose), day 5 (0–24 h postdose), days 9 and 12 (0 h), and day 19 (0–24 h 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 days 1–4 (4 h predose–96 h postdose). Safety was monitored throughout. Results: Forty healthy Chinese subjects (groups 1 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. Conclusion: 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. Clinical Trial Registration: NCT03956953. Plain Language Summary: Deucravacitinib, a new oral medication, blocks an enzyme called tyrosine kinase 2 (TYK2), which is activated in plaque psoriasis. This reduces thick, scaly patches of skin, itching, and other symptoms. How a drug is absorbed and its effects can vary between patients of different races and ethnicities. We studied the safety of deucravacitinib in healthy Chinese volunteers. We also studied how bigger or smaller doses of deucravacitinib change how much of it is absorbed into the blood. We found that most side effects of deucravacitinib were mild or moderate compared to volunteers taking placebo, a look-alike pill that contains no drug. The most common side effects were skin rashes and headaches. No serious side effects were related to deucravacitinib. Deucravacitinib was quickly absorbed into the blood. The time it took for deucravacitinib to reach its maximum amount in the blood was similar regardless of how large of a dose was initially taken. Increasing the amount of deucravacitinib taken also increased the total amount of deucravacitinib absorbed, both in terms of the total amount absorbed and the maximum amount in blood at one time. These results in healthy Chinese volunteers were similar to the results of other studies in a general population of many races and ethnicities. Deucravacitinib works the same in Chinese patients as in patients of other ethnicities. Chinese patients will not need to adjust their dose when taking deucravacitinib. [ABSTRACT FROM AUTHOR]