Purpose Fazamorexant, a dual orexin receptor antagonist (DORA) targeting insomnia, demonstrated in vitro metabolism via CYP3A4. Thus, the effects of CYP3A4 inhibitors on the pharmacokinetics, safety, and tolerability of fazamorexant were investigated. Methods In this single-center, open-label, non-randomized, fixed-sequence study, 24 healthy subjects received a single oral dose of fazamorexant (20 mg) alone on D1, followed by a 6-day regimen of the CYP3A4 weak inhibitor ticagrelor (90 mg twice daily, Days 2 to 7) to reach steady state, with a second dose of fazamorexant co-administered on Day 6. Area under the plasma concentration–time curve from time zero to infinity (AUC0–inf), maximum plasma concentration (Cmax), time to Cmax (Tmax), and other relevant pharmacokinetic parameters were derived from plasma concentrations of fazamorexant collected at prespecified time points. Adverse events (AEs) were recorded. Results CYP3A4 weak inhibition by ticagrelor (90 mg, twice daily) increased the Cmax of fazamorexant by approximately 14% (90% confidence interval (CI): 100.92-129.07), whereas AUC0−t (90% CI: 86.44-125.58), AUC0− inf (90% CI: 85.60-124.53) and Tmax (P = 0.665) remained essentially unchanged. Fazamorexant, whether given alone or in combination with ticagrelor, was generally safe and well tolerated. Conclusion Overall, co-administration of CYP3A4 weak inhibitors with fazamorexant is not expected to result in clinically significant drug interactions, and no dosage adjustment is required when these agents are used concomitantly. Trial registration This trial was registered on the Drug Clinical Trial Registration and Information Disclosure Platform (registration number CTR20242889, accessible at <a href="https://www.chinadrugtrials.org.cn/clinicaltrials.searchlist.dhtml?keywords=CTR20242889">https://www.chinadrugtrials.org.cn/clinicaltrials.searchlist.dhtml?keywords=CTR20242889</a>) on 5 August 2024, and on ClinicalTrials.gov (NCT06671470, accessible at <a href="https://clinicaltrials.gov/ct2/show/NCT06671470">https://clinicaltrials.gov/ct2/show/NCT06671470</a>) on 31 October 2024. The ClinicalTrials.gov registration was retrospective.

Drug-drug interaction between ticagrelor and fazamorexant: pharmacokinetic alterations in healthy subjects from a phase I, open-label, fixed-sequence study

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2026年7月22日

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Xingxing Huang,
Yuzhu Chen,
Lu Jin,
Yanyan Kong,
Fengxia Bao,
Ruwei Wang

摘要

Purpose

Fazamorexant, a dual orexin receptor antagonist (DORA) targeting insomnia, demonstrated in vitro metabolism via CYP3A4. Thus, the effects of CYP3A4 inhibitors on the pharmacokinetics, safety, and tolerability of fazamorexant were investigated.

Methods

In this single-center, open-label, non-randomized, fixed-sequence study, 24 healthy subjects received a single oral dose of fazamorexant (20 mg) alone on D1, followed by a 6-day regimen of the CYP3A4 weak inhibitor ticagrelor (90 mg twice daily, Days 2 to 7) to reach steady state, with a second dose of fazamorexant co-administered on Day 6. Area under the plasma concentration–time curve from time zero to infinity (AUC_0–inf), maximum plasma concentration (C_max), time to C_max (T_max), and other relevant pharmacokinetic parameters were derived from plasma concentrations of fazamorexant collected at prespecified time points. Adverse events (AEs) were recorded.

Results

CYP3A4 weak inhibition by ticagrelor (90 mg, twice daily) increased the C_max of fazamorexant by approximately 14% (90% confidence interval (CI): 100.92-129.07), whereas AUC_0−t (90% CI: 86.44-125.58), AUC_{0− inf} (90% CI: 85.60-124.53) and T_max (P = 0.665) remained essentially unchanged. Fazamorexant, whether given alone or in combination with ticagrelor, was generally safe and well tolerated.

Conclusion

Overall, co-administration of CYP3A4 weak inhibitors with fazamorexant is not expected to result in clinically significant drug interactions, and no dosage adjustment is required when these agents are used concomitantly.

Trial registration

This trial was registered on the Drug Clinical Trial Registration and Information Disclosure Platform (registration number CTR20242889, accessible at https://www.chinadrugtrials.org.cn/clinicaltrials.searchlist.dhtml?keywords=CTR20242889) on 5 August 2024, and on ClinicalTrials.gov (NCT06671470, accessible at https://clinicaltrials.gov/ct2/show/NCT06671470) on 31 October 2024. The ClinicalTrials.gov registration was retrospective.