Dizal Pharmaceuticals, Shanghai, China.
Clinical Pharmacology Research Center, Peking Union Medical College Hospital, State Key Laboratory of Complex Severe and Rare Diseases, NMPA Key Laboratory for Clinical Research and Evaluation of Drug, Beijing, China.
Front Immunol. 2023 Apr 3;14:1127935. doi: 10.3389/fimmu.2023.1127935. eCollection 2023.
Golidocitinib is an orally available, potent and highly selective JAK (Janus kinase)-1 inhibitor of JAK/STAT3 signaling under clinical development for the treatment of cancer and autoimmune diseases. The objectives of the two reported studies were to investigate the pharmacokinetics (PK), safety, and tolerability of golidocitinib in healthy Chinese participants as compared to those healthy Western participants, as well as the food effect exploration.
Two phase I studies (JACKPOT2 and JACKPOT3) were conducted in USA and China, respectively. In JACKPOT2 study, participants were randomized into placebo or golidocitinib arm in single-ascending dose cohorts (5 - 150 mg) and multiple-ascending dose cohorts (25 - 100 mg, once daily) for 14 days. In the food effect cohort, golidocitinib (50 mg) was administrated shortly after a high-fat meal (fed conditions) as compared to under fasting conditions. In JACKPOT3 study conducted in China, participants were randomized to placebo or golidocitinib arm in single-ascending dose cohorts (25 - 150 mg).
Exposure of golidocitinib generally increased in a dose-proportional manner across a dose range of 5 mg to 150 mg (single dose) and 25 mg to 100 mg (once daily). High-fat food did not alter the PK of golidocitinib with statistical significance. Low plasma clearance and extensive volume of distribution characterizes PK of golidoctinib, and long half-life across the dose levels supported once daily dosing. The inter-ethnic difference in primary PK parameters was evaluated. The result suggested slightly higher peak plasma concentrations (C) but comparable area under the plasma concentration-time curve (AUC) was observed in Asian (Chinese) subjects as compared to Caucasian and/or Black subjects, while it was not considered clinically relevant. Golidocitinib was well tolerated without Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or higher drug-related treatment emergent adverse events (TEAE) reported.
No noticeable inter-ethnic difference was observed among Asian, Black, and Caucasian healthy subjects in anticipation of the favorable PK properties of golidocitinib. The effect of food on the bioavailability of golidocitinib was minor following a single oral administration of 50 mg. These data guided to use the same dose and regimen for multinational clinical development.
https://clinicaltrials.gov/ct2/show/NCT03728023?term=NCT03728023&draw=2&rank=1, identifier (NCT03728023); http://www.chinadrugtrials.org.cn/clinicaltrials.searchlistdetail.dhtml, identifier (CTR20191011).
戈利木单抗是一种口服、强效且高度选择性的 JAK（Janus 激酶）-1 抑制剂，正在临床开发中用于治疗癌症和自身免疫性疾病。这两项研究的目的是调查戈利木单抗在中国健康参与者与西方健康参与者中的药代动力学（PK）、安全性和耐受性，以及探索食物对其的影响。
这两项 I 期研究（JACKPOT2 和 JACKPOT3）分别在美国和中国进行。在 JACKPOT2 研究中，参与者按单剂量递增队列（5-150mg）和多剂量递增队列（25-100mg，每日一次）随机分为安慰剂或戈利木单抗组，连续给药 14 天。在食物影响队列中，戈利木单抗（50mg）在高脂肪餐后（进食条件）与空腹条件下相比进行给药。在中国进行的 JACKPOT3 研究中，参与者按单剂量递增队列（25-150mg）随机分为安慰剂或戈利木单抗组。
戈利木单抗的暴露量在 5mg 至 150mg（单剂量）和 25mg 至 100mg（每日一次）的剂量范围内呈剂量比例增加。高脂肪食物对戈利木单抗的 PK 没有统计学意义的影响。低血浆清除率和广泛的分布容积是戈利木单抗 PK 的特征，在各剂量水平下半衰期较长支持每日一次给药。评估了主要 PK 参数的种族间差异。结果表明，与白种人和/或黑种人相比，亚洲（中国人）受试者的峰血浆浓度（C）略高，但血浆浓度-时间曲线下面积（AUC）相似，这并不认为具有临床意义。戈利木单抗耐受性良好，未报告任何不良事件通用术语标准（CTCAE）3 级或更高的药物相关治疗突发不良事件（TEAE）。
在预期戈利木单抗具有良好 PK 特性的情况下，亚洲、黑人和白种健康受试者之间未观察到明显的种族间差异。单次口服 50mg 后，食物对戈利木单抗生物利用度的影响较小。这些数据指导了在跨国临床开发中使用相同的剂量和方案。
