Effect of lemborexant on pharmacokinetics of clozapine: A potential drug–drug interaction mediated by time‐dependent inhibition of CYP3A4

Author:

Watanabe Kenya1,Misaka Shingen12ORCID,Kanno‐Nozaki Keiko3,Chiyoda Takaaki3,Suzuki Yuhei3,Sato Akiko3,Suto Takahiro1,Kuroda Junko1,Shimomura Kenju2ORCID,Miura Itaru3,Yabe Hirooki3ORCID

Affiliation:

1. Department of Pharmacy Fukushima Medical University Hospital Fukushima Japan

2. Department of Bioregulation and Pharmacological Medicine, School of Medicine Fukushima Medical University School of Medicine Fukushima Japan

3. Department of Neuropsychiatry, School of Medicine Fukushima Medical University School of Medicine Fukushima Japan

Abstract

AbstractClozapine (CLZ) is extensively used for treatment‐resistant schizophrenia (TRS) with caution to avoid serious adverse events such as agranulocytosis and drug–drug interactions (DDIs). In the current report, we present a case of a 35‐year‐old male non‐smoking TRS patient whose steady‐state plasma trough concentrations (Ctrough) of CLZ and its active metabolite, N‐desmethylclozapine (NDMC), were significantly increased after initiating oral administration of lemborexant (LEM), a dual orexin receptor antagonist, for the treatment of insomnia. The patient experienced oversedation with sleepiness and fatigue while maintaining high levels of Ctrough of CLZ. The increased concentrations of CLZ returned to normal ranges after the discontinuation of LEM dosing, implying a pharmacokinetic DDI between CLZ and LEM. To gain insight into possible mechanisms, we performed in vitro assays of CYP1A2‐ and CYP3A4‐mediated CLZ metabolism by measuring the formations of NDMC and clozapine N‐oxide (CNO). In accordance with previous studies, the incubation of CLZ with each enzyme resulted in the production of both metabolites. LEM had only a weak inhibitory effect on CYP1A2‐ and CYP3A4‐mediated CLZ metabolism. However, the preincubation of LEM with CYP3A4 in the presence of NADPH showed a significant enhancement of inhibitory effects on CLZ metabolism with IC50 values for the formations of CNO and NDMC of 2.8 μM and 4.1 μM, respectively, suggesting that LEM exerts as a potent time‐dependent inhibitor for CYP3A4. Taken together, the results of the current study indicate that co‐medication of CLZ with LEM may lead to increase in exposure to CLZ and risks of CLZ‐related adverse events.

Publisher

Wiley

Subject

Pharmacology (medical),Pharmacology

Cited by 1 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. Clozapine/lemborexant interaction;Reactions Weekly;2023-10-21

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