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Pharmacokinetics, Pharmacodynamics, and Safety of the Dual Orexin Receptor Antagonist Lemborexant: Findings From Single-Dose and Multiple-Ascending-Dose Phase 1 Studies in Healthy Adults.

ABSTRACT: Lemborexant, a dual orexin receptor antagonist, is approved for the treatment of insomnia and is under investigation for treating other sleep disorders. Here we summarize pharmacokinetic, pharmacodynamic, and safety data from 3 randomized, double-blind, placebo-controlled phase 1 studies: single ascending doses in healthy adults (Study 001; 1-200 mg; N = 64), multiple ascending doses in healthy and elderly adults (Study 002; 2.5-75 mg; N = 55), and multiple doses in healthy white and Japanese adults (Study 003; 2.5-25 mg; N = 32). Lemborexant exposure increased with increasing dose. The time to maximum concentration ranged from approximately 1 to 3 hours for the 5- and 10-mg doses. The mean effective half-life was 17 hours for lemborexant 5 mg and 19 hours for lemborexant 10 mg. The plasma concentration at 9 hours postdose was 27% of the maximum concentration following multiple dosing with lemborexant 10 mg. There were no clinically relevant effects on next-morning residual sleepiness (Karolinska Sleepiness Scale, Digital Symbol Substitution Test, Psychomotor Vigilance Test) for doses through 10 mg/day, indicating no effect of residual plasma concentrations on next-day residual effects. Lemborexant was well tolerated across the doses tested. There were no clinically relevant effects of age, sex, or race on lemborexant pharmacokinetics, pharmacodynamics, or safety. These results suggest that lemborexant at doses through 25 mg provides an overall pharmacokinetic, pharmacodynamic, and safety profile suitable for obtaining the target pharmacologic effect supporting treatment of insomnia while minimizing residual effects during wake time.

SUBMITTER: Landry I

PROVIDER: S-EPMC7891412 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Pharmacokinetics, Pharmacodynamics, and Safety of the Dual Orexin Receptor Antagonist Lemborexant: Findings From Single-Dose and Multiple-Ascending-Dose Phase 1 Studies in Healthy Adults.

Landry Ishani I Nakai Kenya K Ferry Jim J Aluri Jagadeesh J Hall Nancy N Lalovic Bojan B Moline Margaret L ML

Clinical pharmacology in drug development 20200528 2

Lemborexant, a dual orexin receptor antagonist, is approved for the treatment of insomnia and is under investigation for treating other sleep disorders. Here we summarize pharmacokinetic, pharmacodynamic, and safety data from 3 randomized, double-blind, placebo-controlled phase 1 studies: single ascending doses in healthy adults (Study 001; 1-200 mg; N = 64), multiple ascending doses in healthy and elderly adults (Study 002; 2.5-75 mg; N = 55), and multiple doses in healthy white and Japanese ad ...[more]

PMID: 32468649

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Project description:BACKGROUND:Excessive neutrophil presence and activation is important in a number of acute and chronic inflammatory diseases. The CXCR2 chemokine receptor is important in controlling the extravasation and activation of neutrophils. Selective antagonism of the CXCR2 receptor is a potential approach to reducing neutrophil migration and activation. Danirixin, is a small molecule, CXCR2 antagonist being evaluated as a potential anti-inflammatory medicine. METHODS:(1) First time in human (FTIH) double-blind, placebo-controlled study to evaluate the safety, pharmacokinetics, and pharmacodynamics of single ascending and repeat oral doses of danirixin in healthy male subjects; (2) single-dose study of age, gender, food, and proton-pump inhibitor effects on the pharmacokinetics of danirixin in healthy adult subjects; and placebo-controlled study of the pharmacokinetics of danirixin in healthy elderly subjects. RESULTS:There were no serious adverse events and no adverse events considered to be of clinical relevance. There were no withdrawals due to adverse events. Systemic exposure following single doses of danirixin 10 mg, 25 mg, 50 mg, 100 mg, and 200 mg increased with increasing dose. Engagement of pharmacology was demonstrated as inhibition of ex-vivo CXCL1-induced CD11b expression on peripheral blood neutrophils when compared to placebo (approximately 50% for 50 mg and 100 mg danirixin, and 72% at 200 mg). There was a 37% decrease in Cmax and a 16% decrease in AUC (0-?) following administration of danirixin in the presence of food. Cmax also decreased by 65% when danirixin 100 mg was administered following omeprazole 40 mg once daily for 5 days. The AUC (0-?) and Cmax were 50% lower in elderly subjects compared with younger subjects. CONCLUSION:The dose-dependent inhibition of agonist-induced neutrophil activation following single and repeated once daily oral administration of danirixin suggests that this CXCR2 antagonist may have benefit in neutrophil-predominant inflammatory diseases. Co-administration with food, gastric acid reducing agents, and variable exposure in the elderly have important clinical implications that need to be taken into consideration in subsequent clinical evaluations. TRIAL REGISTRATION:ClinicalTrials.gov identifiers: NCT01209052 and NCT01209104.

Dataset Information

Pharmacokinetics, Pharmacodynamics, and Safety of the Dual Orexin Receptor Antagonist Lemborexant: Findings From Single-Dose and Multiple-Ascending-Dose Phase 1 Studies in Healthy Adults.

Publications

Pharmacokinetics, Pharmacodynamics, and Safety of the Dual Orexin Receptor Antagonist Lemborexant: Findings From Single-Dose and Multiple-Ascending-Dose Phase 1 Studies in Healthy Adults.

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