Safety, tolerability, pharmacokinetics, and pharmacodynamics of PF-06650833, a selective interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor, in single and multiple ascending dose randomized phase 1 studies in healthy subjects
Safety, tolerability, pharmacokinetics, and pharmacodynamics of PF-06650833, a selective interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor, in single and multiple ascending dose randomized phase 1 studies in healthy subjects
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DOI：
10.1186/s13075-019-2008-6
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发表时间：
2019-12-05
影响因子：
4.9
通讯作者：
Kilty, Iain
中科院分区：
文献类型：
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作者：
Danto, Spencer, I;Shojaee, Negin;Kilty, Iain
背景：PF-06650833是一种强效、选择性白细胞介素-1受体相关激酶4（IRAK 4）抑制剂。两项随机化、双盲、双盲、开放性I期研究在健康成人受试者中评价了PF-06650833速释（IR）和缓释（MR）口服制剂单次（SAD）和多次递增剂量（MAD）的安全性、药代动力学和药效学。研究1（NCT 02224651）是一项为期96天、安慰剂替代、SAD研究，在空腹和进食状态下每日一次（QD）口服PF-06650833 IR 1 - 6000 mg和MR 30 - 300 mg。研究2（NCT 02485769）是一项为期14天的安慰剂对照MAD研究，PF-06650833 IR 25 - 750 mg每日2次、IR 1000 mg每日4次、IR 330 mg每日3次和MR 300 mg QD。结果：PF-06650833通常耐受良好，在两项研究中均未发现剂量限制性治疗后出现的不良事件（TEAE）。TEAE的严重程度通常为轻度，最常报告的是头痛、胃肠道疾病和痤疮。未报告严重AE或死亡。两项研究均未确定最大耐受剂量。在SAD研究中，食物摄入延迟了IR 30 mg的吸收，并使总暴露量增加了33%。MR制剂实现了延迟吸收（IR 100 mg和MR 100 mg制剂的Tmax分别为1 h和8 h）。食物对MR 30 mg的总暴露量无影响，但半衰期缩短1.8倍，C-max增加62%。在MAD研究中，AUC（tau）的蓄积范围为0.9倍至1.4倍，C-max为0.9倍至1.3倍。在所有剂量组中，尿液中回收的原型药物不到剂量的1%，IR = 250 mg和MR 300 mg的肾脏清除率范围为14 - 23 mL/min< 750 mg and MR 300 mg. There was a sustained decrease in serum high-sensitivity C-reactive protein for IR >。基于胆固醇/羟基胆固醇比，没有明显的CYP 3A诱导或抑制observed.Conclusions：PF-06650833，第一个IRAK 4抑制剂进入临床开发，具有良好的安全性和药代动力学特征，并已显示出药理作用的证据。这些数据支持在治疗风湿性和自身免疫性疾病的人体临床试验中继续进行评价。
Background: PF-06650833 is a potent, selective inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4). Two randomized, double-blind, sponsor-open phase 1 studies evaluated the safety, pharmacokinetics, and pharmacodynamics of single (SAD) and multiple ascending doses (MAD) of PF-06650833 immediate-release (IR) and modified-release (MR) oral formulations in healthy adult subjects.Methods: Study 1 (NCT02224651) was a 96-day, placebo-substitution, SAD study of once-daily (QD) oral PF-06650833 IR 1 to 6000 mg and MR 30 to 300 mg in fasted and fed states. Study 2 (NCT02485769) was a 14-day, placebo-controlled, MAD study of PF-06650833 IR 25 to 750 mg twice daily, IR 1000 mg four times per day, IR 330 mg three times per day, and MR 300 mg QD.Results: PF-06650833 was generally well tolerated, with no dose-limiting treatment-emergent adverse events (TEAEs) identified in either study. TEAEs were generally mild in severity, with headache, gastrointestinal disorders, and acne most commonly reported. No serious AEs or deaths were reported. A maximum tolerated dose was not established in either study. In the SAD study, food intake delayed absorption of IR 30 mg and increased total exposure by 33%. Delayed absorption was achieved with the MR formulation (T-max of 1 h versus 8 h for IR 100 mg and MR 100 mg formulations, respectively). Food had no effect on total exposure for MR 30 mg, but reduced half-life 1.8-fold and increased C-max by 62%. In the MAD study, accumulation ranged from 0.9-fold to 1.4-fold for AUC(tau) and 0.9-fold to 1.3-fold for C-max. Less than 1% of the dose was recovered unchanged in urine for all dose groups, with renal clearance ranging from 14 to 23 mL/min for IR < 750 mg and MR 300 mg. There was a sustained decrease in serum high-sensitivity C-reactive protein for IR >= 250 mg and MR 300 mg. Based on the cholesterol/hydroxycholesterol ratio, no apparent CYP3A induction or inhibition was observed.Conclusions: PF-06650833, the first IRAK4 inhibitor to enter clinical development, has a favorable safety and pharmacokinetic profile and has shown evidence of pharmacological effect. The data support continued evaluation in human clinical trials for the treatment of rheumatic and autoimmune diseases.