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ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Drug Metabolism and Transport
Volume 15 - 2024 |
doi: 10.3389/fphar.2024.1414066
This article is part of the Research Topic New Drugs and Future Challenges in Drug Metabolism and Transport View all articles
A phase I, randomized study to evaluate safety, tolerability, and pharmacokinetic of mefunidone in healthy subjects
Provisionally accepted
Mai Han
1
Shixi Zhang
2*
Gaoyun Hu
3*
Xin Zhang
1*
Gang Cui
1*
Wei Wu
1*
Na Mi
1*
Bishan Huo
2*
Jiangli Jin
1
Xing Lu
1*
Bidong Wu
2*
Chunyan Xiao
1*
Jing Wang
1*
Zheng Bian
1*
Jintong Li
1*- 1 China-Japan Friendship Hospital, Beijing, China
- 2 Guangzhou Nanxin Pharma Co., LTD, Guangzhou, China, Guangzhou, China
- 3 Central South University, Changsha, Hunan Province, China
Background: Mefunidone is a novel synthetic compound and an improvement over pirfenidone for the anti-fibrotic treatment of renal fibrosis in end-stage renal disease. We conducted this first-in-human, phase I clinical trial to determine the safety, tolerability, and pharmacokinetic (including food effect) profiles of mefunidone administered orally as single and multiple ascending doses in healthy subjects. Methods: Part A assessed single ascending doses of mefunidone from 25 mg to 800 mg or placebo once daily in the fasted state. Part A also assessed the effect of food on the tolerability and PK in cohort 100 mg. Part B consisted of 3 treatment groups who received 100 mg, 200 mg or 400 mg of mefunidone or placebo twice daily (BID, bis in die) on Days 1-6, and once in the morning on Day 7. Results: Single oral doses of mefunidone up to 800 mg and multiple doses of mefunidone up to 400 mg BID were all well tolerated. Mefunidone behaved along with ideal dose proportionality within single dose range of 50 mg to 600 mg and multiple dose range of 100 mg BID to 400 mg BID by Day 7. High-fat fed conditions led to a delay in Tmax about 1 hour and a slight reduction of about 20% in Cmax compared to fasted conditions, but didn't significantly affect the systemic exposure. Conclusions: Mefunidone exhibited favorable pharmacokinetics and safety profiles. The present study informed and supported further development clinical study of mefunidone.
Keywords: Mefunidone, pharmacokinetics, First-in-human (FIH), Safety, Food effect
Received: 08 Apr 2024; Accepted: 21 May 2024.
Copyright: © 2024 Han, Zhang, Hu, Zhang, Cui, Wu, Mi, Huo, Jin, Lu, Wu, Xiao, Wang, Bian and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Shixi Zhang, Guangzhou Nanxin Pharma Co., LTD, Guangzhou, China, Guangzhou, China
Gaoyun Hu, Central South University, Changsha, 130012, Hunan Province, China
Xin Zhang, China-Japan Friendship Hospital, Beijing, China
Gang Cui, China-Japan Friendship Hospital, Beijing, China
Wei Wu, China-Japan Friendship Hospital, Beijing, China
Na Mi, China-Japan Friendship Hospital, Beijing, China
Bishan Huo, Guangzhou Nanxin Pharma Co., LTD, Guangzhou, China, Guangzhou, China
Xing Lu, China-Japan Friendship Hospital, Beijing, China
Bidong Wu, Guangzhou Nanxin Pharma Co., LTD, Guangzhou, China, Guangzhou, China
Chunyan Xiao, China-Japan Friendship Hospital, Beijing, China
Jing Wang, China-Japan Friendship Hospital, Beijing, China
Zheng Bian, China-Japan Friendship Hospital, Beijing, China
Jintong Li, China-Japan Friendship Hospital, Beijing, China
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.