Effect of hepatic impairment on pharmacokinetics, safety, and tolerability of lemborexant.

Lemborexant, a dual orexin receptor antagonist, is approved in the United States, Japan, and Canada for the treatment of insomnia in adults. This phase I, multicenter, open-label, parallel-group study assessed the impact of mild or moderate hepatic impairment (HI) on lemborexant pharmacokinetics and metabolism. The pharmacokinetics, tolerability, and safety of lemborexant were evaluated in subjects with mild (Child-Pugh class A) or moderate (Child-Pugh class B) HI and healthy age-, sex-, and body mass index (BMI)-matched control subjects (n = 8 subjects/group). Subjects received a single oral dose of lemborexant 10 mg (LEM10). Blood samples were collected up to 312 hours post dosing for lemborexant pharmacokinetics assessments. Median time to maximum plasma concentration was similar across all groups. Compared with healthy subjects, exposure measures (maximum plasma concentration [Cmax ] and area under the curve extrapolated to infinity [AUC0-inf ]) increased by ~58% (Cmax ) and ~25% (AUC0-inf ) in subjects with mild HI and ~22% (Cmax ) and ~54% (AUC0-inf ) in subjects with moderate HI. Clearance decreased by 20% and 35% in subjects with mild and moderate HI, respectively, versus healthy subjects. Lemborexant unbound fraction was similar in all groups (range: 0.060-0.065). All treatment-emergent adverse events (TEAEs) were mild in severity; no serious TEAEs occurred. In conclusion, following a single LEM10 dose, lemborexant exposure was similar in subjects with mild HI and increased in subjects with moderate HI versus healthy subjects. No dose adjustment is required in subjects with mild HI. Dosing in subjects with moderate HI should be restricted to 5 mg. Lemborexant was well tolerated in all groups.

Investigation of the effect of the dual orexin receptor antagonist almorexant on ophthalmological, spermatogenic, and hormonal variables in healthy male subjects.

BACKGROUND/AIMS: The aim of this single-center, double-blind study was to investigate the effect of a 4-week once daily administration of 200 mg almorexant on tear film break-up time, spermatogenesis, hormone levels, and pancreatic elastase in stool in healthy male subjects. METHODS: Almorexant 200 mg or matching placebo was administered in the evening for 4 weeks once daily to 56 healthy male subjects. Changes in ophthalmological variables, sperm composition, hormone levels, and pancreatic elastase levels in stool were evaluated periodically up to 8 weeks after discontinuation of drug administration. Blood samples for pharmacokinetic measurements were taken after 4 weeks to confirm compliance to study drug intake. RESULTS: The results of this study revealed no treatment effects of almorexant, neither on tear film break-up time nor on other ophthalmological variables investigated during this study. Furthermore, spermatogenesis, hormones of the hypothalamic-pituitary-adrenal and -gonadal axes, and endocrine pancreatic secretion were shown to be not affected by a 4-week once daily administration of almorexant. CONCLUSION: Almorexant was well tolerated and had no effect on the spectrum of pharmacodynamic variables assessed. Ophthalmology and testicular findings detected in preclinical studies were not observed in this clinical study. Therefore, these preclinical findings appear not to be relevant for humans and do not prevent from conducting larger clinical trials with either healthy subjects or patients.

CYP450-Mediated metabolism of suvorexant and investigation of metabolites in forensic case specimens.

Suvorexant (Belsomra®) is a sedative hypnotic that was approved for use in 2015. It has a novel mechanism of action and was the first dual orexin receptor antagonist (DORA) to be approved for the treatment of sleep disorders. Sedative hypnotics often feature prominently in forensic investigations such as impaired driving and drug-facilitated sexual assault (DFSA) cases. As such, suvorexant is a drug of interest and its identification in forensic toxicology investigations is of significance. However, limited studies have been published to date and the disposition or importance of its metabolites has been largely uninvestigated. In this report, we investigate the enzymes responsible for metabolism and explore the prevalence of metabolites in blood from a series of thirteen forensic investigations. Recombinant cytochrome P450 enzymes (rCYPs) were used to generate phase I metabolites for suvorexant in vitro, and metabolites were identified using liquid chromatography-quadrupole/time-of-flight-mass spectrometry (LC-Q/TOF-MS). Four rCYP isoenzymes (3A4, 2C19, 2D6, and 2C9) were found to contribute to suvorexant metabolism. The only metabolite identified in blood or plasma arose from hydroxylation of the benzyl triazole moiety (M9). This metabolite was identified in seventeen blood and plasma specimens from twelve medicolegal death investigations and one impaired driving investigation. In the absence of a commercially available reference material, the metabolite was confirmed using rCYP-generated in vitro controls using high resolution mass spectrometry.

Sleep modulating agents.

Sleep and wake are two fundamental states of human existence. Conditions such as insomnia and hypersomnia can have profound negative effects on human health. Many pharmacological interventions impacting sleep and wake are available or are under development. This brief digest surveys early approaches to sleep modulation and highlights recent developments in sleep modulating agents.

Initial Development toward Non-Invasive Drug Monitoring via Untargeted Mass Spectrometric Analysis of Human Skin.

Drug monitoring is crucial for providing accurate and effective care; however, current methods (e.g., blood draws) are inconvenient and unpleasant. We aim to develop a non-invasive method for the detection and monitoring of drugs via human skin. The initial development toward this aim required information about which drugs, taken orally, can be detected via the skin. Untargeted liquid chromatography-mass spectrometry (LC-MS) was used as it was unclear if drugs, known drug metabolites, or other transformation products were detectable. In accomplishing our aim, we analyzed samples obtained by swabbing the skin of 15 kidney transplant recipients in five locations (forehead, nasolabial area, axillary, backhand, and palm), bilaterally, on two different clinical visits. Untargeted LC-MS data were processed using molecular networking via the Global Natural Products Social Molecular Networking platform. Herein, we report the qualitative detection and location of drugs and drug metabolites. For example, escitalopram/citalopram and diphenhydramine, taken orally, were detected in forehead, nasolabial, and hand samples, whereas N-acetyl-sulfamethoxazole, a drug metabolite, was detected in axillary samples. In addition, chemicals associated with environmental exposure were also detected from the skin, which provides insight into the multifaceted chemical influences on our health. The proof-of-concept results presented support the finding that the LC-MS and data analysis methodology is currently capable of the qualitative assessment of the presence of drugs directly via human skin.

Zolpidem and Gender: Are Women Really At Risk?

BACKGROUND: In 2013 the Food and Drug Administration (FDA) claimed the existence of new data showing women to be at risk for excessive daytime sedation and impaired driving proficiency following bedtime doses of zolpidem. The putative explanation was the reduced metabolic clearance of zolpidem and higher morning blood concentrations in women compared to men. The FDA acted to reduce the recommended dosage for women down to 50% of the dose for men. No other regulatory agency worldwide has taken similar action. METHODS: Gender effects on zolpidem pharmacokinetics, pharmacodynamics, adverse effects, clinical efficacy, and driving performance were evaluated through a further analysis of data from a previous study, together with a literature review. RESULTS: Women had on average 35% lower apparent clearance of zolpidem than men (236 vs 364 mL/min, P < 0.001). This difference was not explained by body weight. In some laboratory studies, women had greater functional impairment than men taking the same dose, but in all studies active drug was not distinguishable from placebo at 8 hours after oral dosage. On-the-road driving studies likewise showed no evidence of driving impairment in men or women at 8 hours after 10 mg of oral immediate-release zolpidem. No clinical trial demonstrated a gender-related difference in clinical efficacy or adverse reactions, and there was no evidence of a particular risk to women. CONCLUSIONS: Dosage reduction in women is not supported by available scientific evidence, and may in fact lead to underdosing and the consequent hazard of inadequately treated insomnia.

Zolpidem and zolpidem phenyl-4-carboxylic acid pharmacokinetics in oral fluid after a single dose.

BACKGROUND: Oral fluid zolpidem detection in the settings of drug-facilitated crime and roadside drug testing indicates recent zolpidem intake. Zolpidem pharmacokinetics in classical biological matrices such as blood and urine have been described; however, reports of such data based on oral fluids are limited. OBJECTIVE: The aim of this study is to describe the pharmacokinetics of zolpidem and its major metabolite zolpidem phenyl-4-carboxylic acid (ZPCA) in oral fluids after intake. METHODS: Ten milligrams of zolpidem tartrate tablets were orally administered to 14 volunteers, and oral fluid samples were collected at various times up to 72 hours and analyzed via liquid chromatography-tandem mass spectrometry (LC-MS/MS) with post-column reagent addition. RESULTS: Both zolpidem and ZPCA could be detected in oral fluid after 1 hour and were rapidly eliminated, with half-lives of 2.77 ± 0.71 hours and 5.11 ± 0.67 hours, respectively. Maximum zolpidem concentrations (36.73 ± 10.89 ng/mL) occurred at 2 ± 0.52 hours, and maximum ZPCA concentrations (0.28 ± 0.16 ng/mL) occurred at 2 ± 0.37 hours. Zolpidem/ZPCA ratios decreased after zolpidem intake, an observation that might be helpful for determining the time of drug use. CONCLUSION: The results showed that the measurement of zolpidem in oral fluid can be used for the non-invasive monitoring of zolpidem consumption and misuse in drug-facilitated crime and roadside drug testing settings.

Disposition and metabolism of [14C]lemborexant, a novel dual orexin receptor antagonist, in rats and monkeys.

The disposition and metabolism of lemborexant, a novel dual orexin receptor antagonist currently under development as a therapeutic agent for insomnia disorder, were evaluated after a single oral administration of [14C]lemborexant in Sprague-Dawley rats (10 mg/kg) and cynomolgus monkeys (3 mg/kg). In both species, [14C]lemborexant was rapidly absorbed: radioactivity concentration in blood peaked at 0.83-1.8 h, and decreased with elimination half-life of 110 h. The radioactivity administered was excreted primarily into faeces, with relatively little excreted into urine. Lemborexant was not detected in bile, urine or faeces, indicating that lemborexant administered orally was completely absorbed from the gastrointestinal tract and that the main elimination pathway was metabolism in both species. In rats, lemborexant was found to be minor in plasma (≤5.2% of total radioactivity), and M9 (hydroxylated form) was the major circulating metabolite. In monkeys, the major circulating components were lemborexant, M4 (N-oxide metabolite), M13 (di-oxidised form), M14 (di-oxidised form) and M16 (glucuronide of mono-oxidised form). In both species, lemborexant was metabolised to various metabolites by multiple pathways, the primary of which was oxidation of the dimethylpyrimidine or fluorophenyl moiety.

Safety, Tolerability, and Pharmacokinetics of Suvorexant: A Randomized Rising-Dose Trial in Healthy Men.

BACKGROUND AND OBJECTIVES: Suvorexant (MK-4305) is an orexin receptor antagonist approved for the treatment of insomnia in the USA and other regions. This randomized, double-blind, placebo-controlled, sequential-panel, Phase 1 trial assessed the safety, tolerability, and pharmacokinetic data following single and multiple dosing of suvorexant in healthy men (aged 18-45 years). METHODS: Within allocated panels, subjects (n = 8) were randomized to receive nightly doses of suvorexant (10, 20, 40, 80, and 100 mg) administered orally for 14 days, or placebo. Safety assessments included daily adverse event (AE) monitoring; pharmacokinetic data were obtained through periodic sampling. RESULTS: Of 40 subjects randomized, 39 completed the trial. The incidence of any AEs in the 10 and 20 mg groups was 67 and 83%, respectively, while 100% of subjects reported AEs in the dose groups of 40, 80, and 100 mg and the placebo group. The most frequently reported AEs were somnolence (n = 19 subjects), fatigue (n = 17), and headache (n = 15). Following single and multiple dosing, median time to reach maximum observed concentration ranged from 1.5 to 4.0 h and the apparent terminal half-life ranged from 7.7 to 14.5 h. Across the investigated doses, accumulation ratios for the area under the concentration-time curve and the maximum observed concentration were independent of dose and ranged from 1.21 to 1.60 and 1.00 to 1.46, respectively. CONCLUSIONS: Suvorexant was generally well tolerated after single and multiple dosing for 14 days. The findings support the once-nightly dosing regimen.

Accelerated Development of the Dual Orexin Receptor Antagonist ACT-541468: Integration of a Microtracer in a First-in-Human Study.

The orexin system regulates sleep and arousal and is targeted by ACT-541468, a new dual orexin receptor antagonist (DORA). Healthy male subjects received a single oral dose of 5-200 mg to assess safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), mass balance, metabolism, and absolute bioavailability utilizing a 14 C-labeled, orally and intravenously (i.v.) administered microtracer. The drug was safe and well tolerated; the PK profile was characterized by quick absorption and elimination, with median time to reach maximum concentration (tmax ) of 0.8-2.8 h and geometric mean terminal half-life (t1/2 ) of 5.9-8.8 h. Clear dose-related effects on the central nervous system were observed at ≥25 mg, indicating a suitable PK-PD profile for a sleep-promoting drug, allowing for rapid onset and duration of action limited to the intended use. This comprehensive first-in-human study created a wealth of data, while saving resources in drug development.

Effects of the orexin receptor antagonist suvorexant on respiration during sleep in healthy subjects.

Suvorexant is an orexin receptor antagonist for treating insomnia. The maximum approved dose in the United States and Japan is 20 mg. We evaluated suvorexant effects on respiration during sleep in a randomized, double-blind, 3-period crossover study of healthy adult men (n = 8) and women (n = 4) ≤ 50 years old who received single-dose suvorexant 40 mg, 150 mg, and placebo. Respiration during sleep was measured by oxygen saturation (SpO2 , primary end point) and the Apnea Hypopnea Index (AHI). The study was powered to detect a reduction greater than 5% in SpO2 . There was no effect of suvorexant on mean SpO2 during sleep. The mean (90%CI) treatment differences versus placebo were -0.3 (-1.2-0.6) for 40 mg and 0.0 (-0.9-0.9) for 150 mg. There were no dose-related trends in individual SpO2 values. Mean SpO2 was >96% for all treatments during total sleep time and during both non-REM and REM sleep. There was no effect of either suvorexant dose on AHI. The mean (90%CI) treatment differences versus placebo were 0.8 (-0.7-2.3) for 40 mg and -0.2 (-1.7-1.3) for 150 mg. Suvorexant was generally well tolerated; there were no serious adverse experiences or discontinuations. These data from healthy subjects suggest that suvorexant lacks clinically important respiratory effects during sleep at doses greater than the maximum recommended dose for treating insomnia.