PMID- 37981596 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20240109 IS - 2193-8210 (Print) IS - 2190-9172 (Electronic) VI - 13 IP - 12 DP - 2023 Dec TI - Pharmacokinetics and Safety of the Tyrosine Kinase 2 Inhibitor Deucravacitinib in Healthy Chinese Subjects. PG - 3153-3164 LID - 10.1007/s13555-023-01050-7 [doi] AB - 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. CI - (c) 2023. The Author(s). FAU - Jing, Shan AU - Jing S AUID- ORCID: 0000-0002-5648-111X AD - Clinical Pharmacology Centre, Beijing Anzhen Hospital, Capital Medical University, Beijing, China. FAU - Lin, Yang AU - Lin Y AUID- ORCID: 0000-0002-3036-3633 AD - Clinical Pharmacology Centre, Beijing Anzhen Hospital, Capital Medical University, Beijing, China. FAU - Dockens, Randy AU - Dockens R AD - Bristol Myers Squibb, 3551 Lawrenceville Road, Princeton, NJ, 08540, USA. FAU - Marchisin, David AU - Marchisin D AD - Bristol Myers Squibb, 3551 Lawrenceville Road, Princeton, NJ, 08540, USA. FAU - He, Bing AU - He B AD - Bristol Myers Squibb, 3551 Lawrenceville Road, Princeton, NJ, 08540, USA. FAU - Girgis, Ihab G AU - Girgis IG AD - Bristol Myers Squibb, 3551 Lawrenceville Road, Princeton, NJ, 08540, USA. FAU - Chimalakonda, Anjaneya AU - Chimalakonda A AD - Bristol Myers Squibb, 3551 Lawrenceville Road, Princeton, NJ, 08540, USA. FAU - Murthy, Bindu AU - Murthy B AD - Bristol Myers Squibb, 3551 Lawrenceville Road, Princeton, NJ, 08540, USA. FAU - Aras, Urvi AU - Aras U AD - Bristol Myers Squibb, 3551 Lawrenceville Road, Princeton, NJ, 08540, USA. Urvi.Aras@bms.com. LA - eng SI - ClinicalTrials.gov/NCT03956953 PT - Journal Article DEP - 20231119 PL - Switzerland TA - Dermatol Ther (Heidelb) JT - Dermatology and therapy JID - 101590450 PMC - PMC10689320 OAB - 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. OABL- eng OTO - NOTNLM OT - Chinese subjects OT - Deucravacitinib OT - Pharmacokinetics OT - Psoriasis OT - Safety OT - Tyrosine kinase 2 inhibitor COIS- Shan Jing and Yang Lin declare that they have no competing interests. Randy Dockens, David Marchisin, Bing He, Bindu Murthy, and Urvi Aras declare that they are employees of and shareholders in Bristol Myers Squibb. Ihab G. Girgis and Anjaneya Chimalakonda declare that they were employees and shareholders in Bristol Myers Squibb at the time of study conduct; Ihab G. Girgis is now an employee of CSL Behring and Anjaneya Chimalakonda is now an employee of Boehringer Ingelheim. EDAT- 2023/11/20 00:43 MHDA- 2023/11/20 00:44 PMCR- 2023/11/19 CRDT- 2023/11/19 23:14 PHST- 2023/06/01 00:00 [received] PHST- 2023/09/25 00:00 [accepted] PHST- 2023/11/20 00:44 [medline] PHST- 2023/11/20 00:43 [pubmed] PHST- 2023/11/19 23:14 [entrez] PHST- 2023/11/19 00:00 [pmc-release] AID - 10.1007/s13555-023-01050-7 [pii] AID - 1050 [pii] AID - 10.1007/s13555-023-01050-7 [doi] PST - ppublish SO - Dermatol Ther (Heidelb). 2023 Dec;13(12):3153-3164. doi: 10.1007/s13555-023-01050-7. Epub 2023 Nov 19.