PMID- 37601041 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20230823 IS - 1663-9812 (Print) IS - 1663-9812 (Electronic) IS - 1663-9812 (Linking) VI - 14 DP - 2023 TI - A phase 1 study of dimdazenil to evaluate the pharmacokinetics, food effect and safety in Chinese healthy subjects. PG - 1226014 LID - 10.3389/fphar.2023.1226014 [doi] LID - 1226014 AB - Background and objective: As a partial positive allosteric modulator of the gamma-aminobutyric acid A (GABAA) receptor, dimdazenil was used for the treatment of insomnia with the potential to alleviate associated side effects compared to full agonists. The objective of this trial is to assess the safety, tolerability, food effect and pharmacokinetics following single and multiple doses of dimdazenil in Chinese healthy subjects. Methods: In this phase 1 trial, 36 healthy subjects aged >/=18 years were assigned to receive a single dose of 1.5, 2.5, or 5 mg dimdazenil, with each dose cohort consisting of 12 subjects, and 14 subjects were assigned to receive a multiple 2.5 mg daily dose of dimdazenil for 5 days. Safety, tolerability, and pharmacokinetic characteristics were evaluated. Results: Of the 50 subjects enrolled and 49 completed the trial, the incidences of treatment-emergent adverse events (AEs) in the single-dose groups of 1.5, 2.5, and 5 mg were 16.7%, 58.3% and 66.7% respectively, while 61.5% in the multiple-dose group. There were no serious AEs, deaths, AEs leading to discontinuation or AEs of requiring clinical intervention in any treatment groups. The most treatment-emergent AEs were dizziness (n = 4, 8.2%), hyperuricemia (n = 2, 6.1%), upper respiratory tract infection (n = 2, 6.1%), diastolic blood pressure decreased (n = 2, 6.1%), blood TG increased (n = 2, 6.1%) and RBC urine positive (n = 2, 6.1%). All AEs were mild-to-moderate and transient, and no severe AEs were documented in any study phase. The PK profile of dimdazenil and its active metabolite Ro46-1927 was linear across 1.5-5 mg oral doses in humans. The median T(max) for dimdazenil was in the range of 0.5-1.5 h, and the apparent terminal t(1/2z) ranged from 3.50 to 4.32 h. Taking Dimdazenil with food may delay T(max) and decrease C(max), without affecting the total exposure (AUC). No relevant accumulations of dimdazenil and Ro 46-1927 were observed in multiple-dose group. Conclusion: Dimdazenil was generally well tolerated in healthy Chinese subjects after single and 5 days-multiple dosing. The pharmacokinetic properties of dimdazenil are compatible with a drug for the treatment of insomnia. Clinical Trial Registration: chinadrugtrials.org.cn, identifier CTR20201978. CI - Copyright (c) 2023 Wang, He, Zhou, Ye, Li, Ma, Chen, Zhang, Lin, Tang, Jin, Jiang and Lin. FAU - Wang, Fei AU - Wang F AD - Phase 1 Clinical Trial Center, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China. AD - Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China. FAU - He, Jingjing AU - He J AD - Shanghai Research Institute, Zhejiang Jingxin Pharmaceutical Co., Ltd., Shanghai, China. FAU - Zhou, Yanling AU - Zhou Y AD - Shanghai Research Institute, Zhejiang Jingxin Pharmaceutical Co., Ltd., Shanghai, China. FAU - Ye, Lijun AU - Ye L AD - Phase 1 Clinical Trial Center, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China. FAU - Li, Bei AU - Li B AD - Phase 1 Clinical Trial Center, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China. FAU - Ma, Zhiyuan AU - Ma Z AD - Phase 1 Clinical Trial Center, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China. FAU - Chen, Chunyan AU - Chen C AD - Shanghai Research Institute, Zhejiang Jingxin Pharmaceutical Co., Ltd., Shanghai, China. FAU - Zhang, Ruoxi AU - Zhang R AD - Shanghai Research Institute, Zhejiang Jingxin Pharmaceutical Co., Ltd., Shanghai, China. FAU - Lin, Zhaocun AU - Lin Z AD - Shanghai Research Institute, Zhejiang Jingxin Pharmaceutical Co., Ltd., Shanghai, China. FAU - Tang, Jinshan AU - Tang J AD - Shanghai Research Institute, Zhejiang Jingxin Pharmaceutical Co., Ltd., Shanghai, China. FAU - Jin, Zhiping AU - Jin Z AD - Zhejiang Jingxin Pharmaceutical Co., Ltd., Shaoxing, China. FAU - Jiang, Yu AU - Jiang Y AD - Shanghai Research Institute, Zhejiang Jingxin Pharmaceutical Co., Ltd., Shanghai, China. FAU - Lin, Nengming AU - Lin N AD - Phase 1 Clinical Trial Center, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China. AD - Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China. AD - West lake Laboratory of Life Sciences and Biomedicine of Zhejiang Province, Hangzhou, China. AD - Cancer Center, Zhejiang University, Hangzhou, China. LA - eng PT - Journal Article DEP - 20230801 PL - Switzerland TA - Front Pharmacol JT - Frontiers in pharmacology JID - 101548923 PMC - PMC10432719 OTO - NOTNLM OT - GABAA receptor OT - dimdazenil OT - insomnia OT - partial positive allosteric agonist OT - pharmacokinetics OT - safety COIS- The authors declare that this study received funding from Zhejiang Jingxin Pharmaceutical Co., Ltd. The funder had the following involvement in the study: study design, conduct, data collection, management, analysis, and interpretation. EDAT- 2023/08/21 06:42 MHDA- 2023/08/21 06:43 PMCR- 2023/08/01 CRDT- 2023/08/21 04:54 PHST- 2023/05/20 00:00 [received] PHST- 2023/07/17 00:00 [accepted] PHST- 2023/08/21 06:43 [medline] PHST- 2023/08/21 06:42 [pubmed] PHST- 2023/08/21 04:54 [entrez] PHST- 2023/08/01 00:00 [pmc-release] AID - 1226014 [pii] AID - 10.3389/fphar.2023.1226014 [doi] PST - epublish SO - Front Pharmacol. 2023 Aug 1;14:1226014. doi: 10.3389/fphar.2023.1226014. eCollection 2023.