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Population Pharmacokinetics and Exposure-Response Analyses for the Most Frequent Adverse Events Following Treatment With Lemborexant, an Orexin Receptor Antagonist, in Subjects With Insomnia Disorder.

ABSTRACT: Lemborexant is a novel orexin receptor antagonist approved in the United States and Japan for the treatment of insomnia. This article describes the population pharmacokinetics (PK) of lemborexant and the relationship of its daily steady-state exposure (Cav,ss ) to the probability of most frequent treatment-emergent adverse events (TEAEs). The 12 230-observation, 1892-subject PK data set included data from 12 clinical studies with predominantly female subjects (66%) ranging in age from 18 to 88 years and from 37 to 168 kg in body weight. The 1664-subject exposure-response data set included data from 3 late-stage studies. Lemborexant pharmacokinetics were described by a 3-compartment model with combined first- and zero-order absorption with lag time and linear elimination. Oral clearance decreased with increasing body mass index (exponent, -0.428), increasing alkaline phosphatase levels (exponent, -0.118), and was 26% lower in the elderly (?65 years). Across the adverse event analysis, the frequency of subjects experiencing TEAEs during active treatment ranged from approximately 3% to 8%, in the range estimated for placebo. With and without adjustment for age, lemborexant exposure (Cav,ss ) was not a clinically meaningful linear predictor of the probability of specific TEAEs: somnolence, nasopharyngitis, flu/influenza, urinary tract infection, upper respiratory tract infection, or headache. Given the small effect sizes of covariates of the PK model and a low degree of association of lemborexant TEAEs and exposure over the range of phase 3 (therapeutic) 5- and 10-mg doses, lemborexant can be safely administered without the need for dose adjustment.

SUBMITTER: Lalovic B

PROVIDER: S-EPMC7689791 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Population Pharmacokinetics and Exposure-Response Analyses for the Most Frequent Adverse Events Following Treatment With Lemborexant, an Orexin Receptor Antagonist, in Subjects With Insomnia Disorder.

Lalovic Bojan B Majid Oneeb O Aluri Jagadeesh J Landry Ishani I Moline Margaret M Hussein Ziad Z

Journal of clinical pharmacology 20200714 12

Lemborexant is a novel orexin receptor antagonist approved in the United States and Japan for the treatment of insomnia. This article describes the population pharmacokinetics (PK) of lemborexant and the relationship of its daily steady-state exposure (C<sub>av,ss</sub> ) to the probability of most frequent treatment-emergent adverse events (TEAEs). The 12 230-observation, 1892-subject PK data set included data from 12 clinical studies with predominantly female subjects (66%) ranging in age from ...[more]

PMID: 32666570

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Project description:To identify dose(s) of lemborexant that maximize insomnia treatment efficacy while minimizing next-morning residual sleepiness and evaluate lemborexant effects on polysomnography (PSG) measures (sleep efficiency [SE], latency to persistent sleep [LPS], and wake after sleep onset [WASO]) at the beginning and end of treatment.Adults and elderly subjects with insomnia disorder per the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition were enrolled in a multicenter, randomized, double-blind, placebo-controlled, Bayesian, adaptive, parallel-group study, receiving lemborexant (1, 2.5, 5, 10, 15, 25 mg) or placebo for 15 nights. Efficacy assessments included a utility function that combined efficacy (SE) and safety (residual morning sleepiness as measured by Karolinska Sleepiness Scale [KSS]), PSG measures, and sleep diary. Safety assessments included KSS, Digit Symbol Substitution Test, computerized reaction time tests, and adverse events (AEs).A total of 616 subjects were screened; 291 were randomized. Baseline characteristics were similar between lemborexant groups and placebo (?63% female, median age: 49.0 years). The study was stopped for early success after the fifth interim analysis when the 15-mg dose met utility index/KSS criteria for success; 3 other doses also met the criteria. Compared with placebo, subjects showed significant improvements in SE, subjective SE, LPS, and subjective sleep onset latency at the beginning and end of treatment for lemborexant doses ? 5 mg (P < .05). WASO and subjective WASO showed numerically greater improvements for doses > 1 mg. AEs, mostly mild to moderate, included dose-related somnolence.Lemborexant doses ranging from 2.5-10 mg provided efficacy for the treatment of insomnia while minimizing next-morning residual sleepiness.Title: A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group, Bayesian Adaptive Randomization Design, Dose Response Study of the Efficacy of E2006 in Adults and Elderly Subjects With Chronic Insomnia; URL: https://clinicaltrials.gov/ct2/show/NCT01995838; Identifier: NCT01995838.

Project description:Background: Intubation of neonates is difficult and hazardous. Factors associated with procedure-related adverse events and unsuccessful intubation attempts are insufficiently evaluated, especially during neonatal nasotracheal intubations. Objective: Aim of this study was to determine the frequency of tracheal intubation-associated events (TIAEs) during neonatal nasotracheal intubations and to identify factors associated with TIAEs and unsuccessful intubation attempts in our neonatal unit. Methods: This was a prospective, single-site, observational study from May 2017 to November 2019, performed at a tertiary care neonatal intensive care unit in a German academic teaching hospital. All endotracheal intubation encounters performed by the neonatal team were recorded. Results: Two hundred and fifty-eight consecutive intubation encounters in 197 patients were analyzed. One hundred and forty-eight (57.4%) intubation encounters were associated with at least one TIAE. Intubation inexperience (<10 intubation encounters) (OR = 2.15; 95% CI, 1.257-3.685) and equipment problems (OR = 3.43; 95% CI, 1.12-10.52) were predictive of TIAEs. Intubation at first attempt (OR = 0.10; 95% CI, 0.06-0.19) and videolaryngoscopy (OR = 0.47; 96% CI, 0.25-0.860) were predictive of intubation encounters without TIAEs. The first intubation attempt was commonly done by pediatric residents (67.8%). A median of two attempts were performed until successful intubation. Restricted laryngoscopic view (OR = 3.07; 95% CI, 2.08-4.53; Cormack-Lehane grade 2 vs. grade 1), intubation by pediatric residents when compared to neonatologists (OR = 1.74; 95% CI, 1.265-2.41) and support by less experienced neonatal nurses (OR = 1.60; 95% CI, 1.04-2.46) were associated with unsuccessful intubation attempts. Conclusions: In our unit, TIAEs and unsuccessful intubation attempts occurred frequently during neonatal nasotracheal intubations. To improve success rates, quality improvement und further research should target interprofessional education and training, equipment problems and videolaryngoscopy.

Dataset Information

Population Pharmacokinetics and Exposure-Response Analyses for the Most Frequent Adverse Events Following Treatment With Lemborexant, an Orexin Receptor Antagonist, in Subjects With Insomnia Disorder.

Publications

Population Pharmacokinetics and Exposure-Response Analyses for the Most Frequent Adverse Events Following Treatment With Lemborexant, an Orexin Receptor Antagonist, in Subjects With Insomnia Disorder.

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