Randomized, double-blinded, placebo-controlled phase I study of the pharmacokinetics, pharmacodynamics, and safety of KL130008, a novel oral JAK inhibitor, in healthy subjects

Li, Na; Du, Shizheng; Wang, Ying; Zhu, Xiaohong; Shu, Shiqing; Men, Yuchun; He, Miao; Fang, Fang; Wang, Yongsheng; Gong, Yimou; Chen, Jing; Gu, Liling; Cheng, Yezhe; He, Qing; Lu, Hongzhou; Niu, Yuanyuan; Xu, Ying; Feng, Ping

doi:10.1016/j.ejps.2022.106257

Cited by 5 publications

(4 citation statements)

References 18 publications

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“…Regarding safety, WXFL10203614 was well tolerated in all subjects under fed or fasted condition. The TEAEs were consistent with previous studies of WXFL10203614 and JAK inhibitors ( Shi et al, 2014 ; Taylor et al, 2017 ; Choy, 2019 ; Li et al, 2022 ). All TEAEs were mild and resolved spontaneously without any intervention.…”

Section: Discussionsupporting

confidence: 90%

The effect of food on the pharmacokinetics of WXFL10203614, a potential selective JAK1 inhibitor, in healthy Chinese subjects

Huang

Shi²,

Chu³

et al. 2022

Front. Pharmacol.

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Objective: This study was performed to investigate the effect of food on the pharmacokinetics (PK) of WXFL10203614 in healthy Chinese subjects.Methods: This was a randomized, open-label, single-dose, two-treatment (fed vs fasted), two-period, two-sequence, crossover study. 14 eligible subjects were averagely randomized into 2 sequences and then received 10 mg WXFL10203614 under fasted or fed condition. In each period, the blood samples were collected from 0 h (pre-dose) and serially up to 72 h post-dose, and plasma concentrations were detected using the high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method. The effect of food on the PK profile and safety of WXFL10203614 were assessed.Results: 70 subjects were screened, and 14 subjects (10 male and 4 female) were enrolled and completed the study. Under the fasted condition, WXFL10203614 was absorbed rapidly with a Tmax of 0.98 h. The absorption rate was slower, Tmax delayed by 2.98 h, and the Cmax decreased by 16.3% when WXFL10203614 administered after the high-fat and high-calorie diet, other PK parameters were not affected. The 90% confidence intervals (CIs) for the ratio (fed/fasted) of geometric means of the Cmax, AUC0-t and AUC0-∞ were 0.73–1.01, 0.90–1.03 and 0.90–1.03, indicating that the high-fat and high-calorie diet might impact the absorption process of WXFL10203614. Although the Cmax was slightly decreased, there was no significant difference in the Cmax under fasted and fed conditions. Thus, it was not considered clinically significant owing to the small magnitude of changes in Cmax. All Treatment-emergent adverse events (TEAEs) were mild and resolved spontaneously without treatment.Conclusion: Food had no clinically relevant effects on drug system exposure of WXFL10203614. It was well tolerated under fasted and fed conditions in healthy Chinese subjects, so WXFL10203614 could be administered orally with or without food.Clinical Trial Registration: http://www.chinadrugtrials.org.cn/index.html, identifier CTR20191636.

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Section: Discussionsupporting

confidence: 90%

The effect of food on the pharmacokinetics of WXFL10203614, a potential selective JAK1 inhibitor, in healthy Chinese subjects

Huang

Shi²,

Chu³

et al. 2022

Front. Pharmacol.

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“…The study showed that WXFL10203614 was well-tolerated after a single dose and multiple doses. The most frequent AEs were polyuria, the proportion of neutrophils decreased, fecal occult blood (positive for transferrin), neutrophil count decreased, white blood cell count decreased and creatinine increased, most of which were more common with the higher doses, and have previously been reported in healthy subjects or patients treated with JAK inhibitors (Shi et al, 2014;Taylor et al, 2017;Li et al, 2022). As for polyuria and fecal occult blood (positive for transferrin), they were not reported in JAK inhibitor before and the incidence was not associated with the increasing dose of WXFL10203614.…”

Section: Discussionmentioning

confidence: 78%

Safety, tolerability and pharmacokinetics of WXFL10203614 in healthy Chinese subjects: A randomized, double-blind, placebo-controlled phase Ⅰ study

Huang

Ding²,

Que³

et al. 2022

Front. Pharmacol.

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Objective: This study was conducted to investigate the safety, tolerability and pharmacokinetics (PK) of WXFL10203614 after single and multiple oral doses in healthy Chinese subjects.Methods: A single-center, randomized, double-blind, placebo-controlled phase Ⅰ study was performed on healthy Chinese subjects. In the single-dose study, Subjects were randomized into 7 dose levels of WXFL10203614 (1 mg group, n = 2; 2, 5, 10, 17, 25 and 33 mg groups with placebo, 8 subjects per group, 2 of them given placebo). In the multiple-dose study, subjects received 5 or 10 mg WXFL10203614 once daily (QD), 5 mg twice daily (BID) or placebo for 7 consecutive days. Safety, tolerability and PK of WXFL10203614 were all assessed.Results: A total of 592 subjects were screened, 50 subjects were enrolled in the single-dose study and 30 in the multiple-dose study. All adverse events (AEs) were mild or moderate and resolved spontaneously. No Serious Adverse Events (SAEs) or deaths were reported during the study. WXFL10203614 was absorbed rapidly after dosing with Tmax of 0.48–0.98 h, Cmax, AUC0-t and AUC0-∞ were all increased in a dose-related manner over the range of 1–33 mg. Renal excretion was the major route of elimination of WXFL10203614. Steady-state PK parameters (Cmax,ss, AUC0-t,ss and AUC0-∞,ss) were elevated after once-daily administration of 5–10 mg WXFL10203614 and non- and weak drug accumulations were observed, whereas moderate drug accumulation occurred in the 5 mg BID group.Conclusion: WXFL10203614 exhibited good safety, tolerability and favorable PK profiles in healthy Chinese subjects, supporting further clinical development in patients with rheumatoid arthritis.Clinical Trials Registration Number:http://www.chinadrugtrials.org.cn/index.html, #CTR20190069 and CTR20200143.

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“…JAKinibs have evolved in multiple ways since the first generation, with efforts to improve selectivity and pharmacokinetics such as prolonged half-life 105 . Several relatively selective JAK1 inhibitors have been generated (Fig.…”

Section: Jak Family Kinase Inhibitorsmentioning

confidence: 99%

Protein kinases: drug targets for immunological disorders

et al. 2023

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Protein kinases play a major role in cellular activation processes, including signal transduction by diverse immunoreceptors. Given their roles in cell growth and death and in the production of inflammatory mediators, targeting kinases has proven to be an effective treatment strategy, initially as anticancer therapies, but shortly thereafter in immune-mediated diseases. Herein, we provide an overview of the status of small molecule inhibitors specifically generated to target protein kinases relevant to immune cell function, with an emphasis on those approved for the treatment of immune-mediated diseases. The development of inhibitors of Janus kinases that target cytokine receptor signalling has been a particularly active area, with Janus kinase inhibitors being approved for the treatment of multiple autoimmune and allergic diseases as well as COVID-19. In addition, TEC family kinase inhibitors (including Bruton’s tyrosine kinase inhibitors) targeting antigen receptor signalling have been approved for haematological malignancies and graft versus host disease. This experience provides multiple important lessons regarding the importance (or not) of selectivity and the limits to which genetic information informs efficacy and safety. Many new agents are being generated, along with new approaches for targeting kinases.

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Randomized, double-blinded, placebo-controlled phase I study of the pharmacokinetics, pharmacodynamics, and safety of KL130008, a novel oral JAK inhibitor, in healthy subjects

Cited by 5 publications

References 18 publications

The effect of food on the pharmacokinetics of WXFL10203614, a potential selective JAK1 inhibitor, in healthy Chinese subjects

The effect of food on the pharmacokinetics of WXFL10203614, a potential selective JAK1 inhibitor, in healthy Chinese subjects

Safety, tolerability and pharmacokinetics of WXFL10203614 in healthy Chinese subjects: A randomized, double-blind, placebo-controlled phase Ⅰ study

Protein kinases: drug targets for immunological disorders

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