The Pharmacokinetic Profile of Palovarotene: An Open-Label Phase I Trial Investigating the Effect of Food and Potential for Drug-Drug Interaction in Healthy Participants.

IF 1.9 4区 医学 Q3 PHARMACOLOGY & PHARMACY
Rose Marino, Louise Dube, Julien Ogier, Kim-Hanh Le Quan Sang
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引用次数: 0

Abstract

Background and objectives: Palovarotene is under development for the treatment of fibrodysplasia ossificans progressiva (FOP). The objectives of this study were to evaluate palovarotene pharmacokinetics under fed versus fasted conditions and its induction potential towards cytochrome P450 3A4 (CYP3A4) substrate, midazolam.

Methods: In this phase I, open-label trial (NCT04829773), palovarotene pharmacokinetics were characterized after repeated once-daily dosing. In one cohort, healthy participants received three doses of palovarotene 20 mg on Days 1, 6, and 11, as whole capsules under fasted or fed conditions, or sprinkled on food under fed conditions. In another cohort, individuals received midazolam 2 mg on Days 1 and 15 and a daily dose of palovarotene 20 mg on Days 2-15. Palovarotene and midazolam pharmacokinetics, including area under the concentration-time curve from time zero to infinity (AUC(0-∞)) and maximum observed plasma drug concentration (Cmax), were assessed. Adverse events (AEs) were recorded.

Results: Overall, 23 participants completed each part. Palovarotene Cmax and AUC(0-∞) increased by 16.5% and 39.7% under fed versus fasted conditions. Pharmacokinetics were comparable between the whole capsule and sprinkled on food, under fed conditions. Midazolam AUC(0-∞) and Cmax decreased by 13.3% and 9.7% upon palovarotene co-administration over 14 days, less than that required to be considered a weak CYP3A4 inducer. Plasma palovarotene exposures were comparable after single and multiple doses. No serious AEs were reported.

Conclusions: These data support palovarotene administration after a meal, as a whole capsule or sprinkled on food. Palovarotene at 20 mg/day is a not a clinical inducer of CYP3A4. These results provide insights into palovarotene pharmacokinetics, aiding optimization of administration for patients with FOP.

Clinical trials registration number: NCT04829773.

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帕洛沃汀的药代动力学概况:一项研究健康参与者食物影响和药物相互作用潜力的开放标签I期试验。
背景和目的:Palovarotene正在开发中,用于治疗进行性骨化性纤维发育不良(FOP)。本研究的目的是评估帕洛沃汀在喂食和禁食条件下的药代动力学及其对细胞色素P4503A4(CYP3A4)底物咪达唑仑的诱导潜力。方法:在这项I期开放标签试验(NCT04829773)中,每天重复给药一次后,对帕洛洛坦的药代动力学进行表征。在一个队列中,健康参与者在第1天、第6天和第11天接受了三剂20 mg的帕洛沃汀,在禁食或喂食条件下作为整粒胶囊,或在喂食条件下撒在食物上。在另一个队列中,个体在第1天和第15天接受2 mg咪达唑仑,在第2-15天接受20 mg帕洛沃汀的日剂量。评估帕洛洛洛汀和咪达唑仑的药代动力学,包括从时间零点到无穷大的浓度-时间曲线下面积(AUC(0-∞))和最大观察到的血浆药物浓度(Cmax)。记录不良事件(AE)。结果:总体而言,23名参与者完成了每个部分。Palovarotene Cmax和AUC(0-∞)在喂食和禁食条件下分别增加了16.5%和39.7%。在喂食条件下,整个胶囊和撒在食物上的药物动力学具有可比性。帕洛沃洛汀联合给药14天后,咪唑安定AUC(0-∞)和Cmax分别下降了13.3%和9.7%,低于被认为是弱CYP3A4诱导剂所需的水平。单次和多次给药后,帕洛沃汀的血浆暴露量具有可比性。未报告严重不良事件。结论:这些数据支持饭后服用帕洛沃汀,作为一个完整的胶囊或撒在食物上。20 mg/天的帕洛沃汀不是CYP3A4的临床诱导剂。这些结果为帕洛沃汀的药代动力学提供了见解,有助于FOP患者的给药优化。临床试验注册号:NCT04829773。
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来源期刊
CiteScore
3.70
自引率
0.00%
发文量
64
审稿时长
>12 weeks
期刊介绍: Hepatology International is a peer-reviewed journal featuring articles written by clinicians, clinical researchers and basic scientists is dedicated to research and patient care issues in hepatology. This journal focuses mainly on new and emerging diagnostic and treatment options, protocols and molecular and cellular basis of disease pathogenesis, new technologies, in liver and biliary sciences. Hepatology International publishes original research articles related to clinical care and basic research; review articles; consensus guidelines for diagnosis and treatment; invited editorials, and controversies in contemporary issues. The journal does not publish case reports.
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