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.
Rose Marino, Louise Dube, Julien Ogier, Kim-Hanh Le Quan Sang
{"title":"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.","authors":"Rose Marino, Louise Dube, Julien Ogier, Kim-Hanh Le Quan Sang","doi":"10.1007/s13318-023-00856-2","DOIUrl":null,"url":null,"abstract":"<p><strong>Background and objectives: </strong>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.</p><p><strong>Methods: </strong>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<sub>(0-∞)</sub>) and maximum observed plasma drug concentration (C<sub>max</sub>), were assessed. Adverse events (AEs) were recorded.</p><p><strong>Results: </strong>Overall, 23 participants completed each part. Palovarotene C<sub>max</sub> and AUC<sub>(0-∞)</sub> 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<sub>(0-∞)</sub> and C<sub>max</sub> 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.</p><p><strong>Conclusions: </strong>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.</p><p><strong>Clinical trials registration number: </strong>NCT04829773.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":1.9000,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10624720/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"European Journal of Drug Metabolism and Pharmacokinetics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s13318-023-00856-2","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2023/10/7 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
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.
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.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
