帕罗维罗替治疗药物监测：一项开放标签 I 期临床试验，旨在调查健康受试者中食物的影响和药物相互作用的潜力。
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.
机构信息
Ipsen, Cambridge, MA, USA.
Pleiades Consultation Inc., Phoenix, AZ, USA.
出版信息
Eur J Drug Metab Pharmacokinet. 2023 Nov;48(6):691-707. doi: 10.1007/s13318-023-00856-2. Epub 2023 Oct 7.
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) and maximum observed plasma drug concentration (C), were assessed. Adverse events (AEs) were recorded.
RESULTS
Overall, 23 participants completed each part. Palovarotene C and AUC 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 and C 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.
背景与目的
帕罗伐罗替在纤维性骨发育不良进展性（FOP）的治疗中正在研发中。本研究的目的是评估在进食与禁食条件下帕罗伐罗替的药代动力学，并评估其对细胞色素 P450 3A4（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，通过重复每日一次给药来描述帕罗伐罗替的药代动力学。在一个队列中，健康参与者在第 1、6 和 11 天分别接受了三剂 20 mg 帕罗伐罗替，空腹或进食条件下给予完整胶囊，或在进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 天接受了咪达唑仑 2mg，并在第 2-15 天接受了每日 20mg 帕罗伐罗替。评估了帕罗伐罗替和咪达唑仑的药代动力学，包括从零时到无穷大的浓度-时间曲线下面积（AUC）和最大观察到的血浆药物浓度（C）。记录不良事件（AE）。
结果
共有 23 名参与者完成了每个部分。与禁食相比，进食条件下帕罗伐罗替的 C 和 AUC 增加了 16.5%和 39.7%。在进食条件下，完整胶囊和撒在食物上的药代动力学相似。咪达唑仑 AUC 和 C 在 14 天内与帕罗伐罗替联合给药时分别降低了 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，血浆帕罗伐罗替暴露量相当。未报告严重不良事件。
结论
这些数据支持餐后给予整粒胶囊或撒在食物上的帕罗伐罗替。每天 20mg 的帕罗伐罗替不是 CYP3A4 的临床诱导剂。这些结果提供了帕罗伐罗替药代动力学的见解，有助于为 FOP 患者优化给药方案。
临床试验注册号
NCT04829773。
Zotero 插件