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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.

Apixaban is an oral small‐molecule, direct factor Xa (FXa) inhibitor approved in adults for treatment of deep vein thrombosis and pulmonary embolism, and for reducing risk of venous thromboembolism recurrence after initial anticoagulant therapy. This phase I study (NCT01707394) evaluated the pharmacokinetics (PKs), pharmacodynamics (PDs), and safety of apixaban in pediatric subjects (<18 years), enrolled by age group, at risk of venous or arterial thrombotic disorder. A single apixaban dose, targeting adult steady‐state exposure with apixaban 2.5 mg, was administered using two pediatric formulations: 0.1 mg sprinkle capsule (age <28 days); 0.4 mg/ml solution (age 28 days to <18 years; dose range, 1.08–2.19 mg/m2). End points included safety, PKs, and anti‐FXa activity. For PKs/PDs, four to six blood samples were collected ≤26 h postdosing. A population PK model was developed with data from adults and pediatric subjects. Apparent oral clearance (CL/F) included fixed maturation function based on published data. From January 2013 to June 2019, 49 pediatric subjects received apixaban. Most adverse events were mild/moderate, and the most common was pyrexia (n = 4/15). Apixaban CL/F and apparent central volume of distribution increased less than proportionally with body weight. Apixaban CL/F increased with age, reaching adult values in subjects aged 12 to <18 years. Maturation affected CL/F most notably in subjects aged <9 months. Plasma anti‐FXa activity values were linearly related to apixaban concentrations, with no apparent age‐related differences. Pediatric subjects tolerated single apixaban doses well. Study data and population PK model supported phase II/III pediatric trial dose selection.

Background This was an open-label, phase I, nonrandomized, single-sequence, crossover study to evaluate the effect of concomitant administration of multiple doses of clarithromycin on the single-dose exposure, safety, and tolerability of apixaban in healthy subjects. Methods In total, 19 subjects received a single oral dose of apixaban 10 mg on day 1. On day 4, subjects began receiving oral clarithromycin immediate release (IR) 500 mg twice daily (bid) for 4 days. On day 8, subjects received oral apixaban 10 mg and oral clarithromycin IR 500 mg bid. Oral clarithromycin IR 500 mg bid was given alone on days 9 and 10. Results Compared with apixaban alone, coadministration of apixaban with clarithromycin resulted in increased apixaban exposure. The adjusted geometric mean ratio (GMR) was 1.299 (90% confidence interval [CI] 1.220–1.384) for peak plasma concentration ( C max ), whereas the adjusted GMR for the area under the concentration curve (AUC (INF) ) was 1.595 (90% CI 1.506–1.698). The mean half-life and median time to C max of apixaban were comparable with and without concomitant administration of clarithromycin. Administration of apixaban and clarithromycin concomitantly did not result in increased adverse events compared with administration of either agent alone. All adverse events were mild in intensity. Conclusions Apixaban C max and AUC (INF) increased 30% and 60%, respectively, when multiple doses of clarithromycin were coadministered with apixaban versus administration of apixaban alone. The increase in apixaban C max and AUC (INF) with concomitant clarithromycin was less than that which has been observed when apixaban was given with ketoconazole. Administration of apixaban alone and in combination with clarithromycin bid was safe and generally well-tolerated by the healthy adult subjects in this study. Clinical Trial Registration ClinicalTrials.gov identifier number NCT02912234.