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1.
Biomed Pharmacother ; 133: 110955, 2021 Jan.
Article in English | MEDLINE | ID: mdl-33190032

ABSTRACT

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.


Subject(s)
Acetamides/administration & dosage , Hormones/blood , Isoquinolines/administration & dosage , Lacrimal Apparatus/drug effects , Orexin Receptor Antagonists/administration & dosage , Sleep Aids, Pharmaceutical/administration & dosage , Spermatogenesis/drug effects , Acetamides/adverse effects , Acetamides/blood , Acetamides/pharmacokinetics , Administration, Oral , Adult , Biomarkers/blood , Double-Blind Method , Drug Administration Schedule , Healthy Volunteers , Humans , Isoquinolines/adverse effects , Isoquinolines/blood , Isoquinolines/pharmacokinetics , Lacrimal Apparatus/physiology , Male , Orexin Receptor Antagonists/adverse effects , Orexin Receptor Antagonists/blood , Orexin Receptor Antagonists/pharmacokinetics , Patient Safety , Prospective Studies , Risk Assessment , Sleep Aids, Pharmaceutical/adverse effects , Sleep Aids, Pharmaceutical/blood , Sleep Aids, Pharmaceutical/pharmacokinetics , South Africa , Tears , Time Factors , Young Adult
2.
Drug Metab Dispos ; 49(1): 31-38, 2021 01.
Article in English | MEDLINE | ID: mdl-33144331

ABSTRACT

Lemborexant is a novel dual orexin receptor antagonist recently approved for the treatment of insomnia in the United States and Japan. Here, disposition and metabolic profiles were investigated in healthy human subjects. After single oral administration of 10 mg [14C]lemborexant (100 µCi), plasma concentrations of lemborexant and radioactivity peaked at 1 hour postdose and decreased biphasically. Cumulative recovery of the administered radioactivity within 480 hours was 86.5% of the dose, with 29.1% in urine and 57.4% in feces. Unchanged lemborexant was not detected in urine but accounted for 13.0% of the dose in feces, suggesting that the main elimination pathway of lemborexant was metabolism. Metabolite analyses revealed that the major metabolic pathways of lemborexant are oxidation of the dimethylpyrimidine moiety and subsequent further oxidation and/or glucuronidation. In plasma, lemborexant was the dominant component, accounting for 26.5% of total drug-related exposure. M4, M9, M10, and M18 were detected as the major radioactive components; M10 was the only metabolite exceeding 10% of total drug-related exposure. Although M4, M9, and M10 showed binding affinity for orexin receptors comparable to that of lemborexant, their contributions to the sleep-promoting effects of lemborexant are likely low because of the limited brain penetration by P-glycoprotein. Exposure comparison between humans and nonclinical toxicology species confirmed that plasma exposure of M10 was higher in at least one animal species compared with that in humans, indicating that there is no disproportionate metabolite in humans, as defined by International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use M3(R2) and U.S. Food and Drug Administration Metabolite in Safety Testing guidance; therefore, no additional toxicology studies are needed. SIGNIFICANCE STATEMENT: This study provides detailed data of the disposition and metabolism of lemborexant, a novel therapeutic drug for insomnia, in humans, as well as a characterization of the circulating metabolites and assessment of their contributions to efficacy and safety. The information presented herein furthers our understanding of the pharmacokinetic profiles of lemborexant and its metabolites and will promote the safe and effective use of lemborexant in the clinic.


Subject(s)
Drug Monitoring/methods , Pyridines , Pyrimidines , Sleep Initiation and Maintenance Disorders/drug therapy , Administration, Oral , Healthy Volunteers , Humans , Metabolic Networks and Pathways , Orexin Receptor Antagonists/blood , Orexin Receptor Antagonists/pharmacokinetics , Pharmacokinetics , Pyridines/blood , Pyridines/pharmacokinetics , Pyrimidines/blood , Pyrimidines/pharmacokinetics , Radioactivity
3.
J Clin Pharmacol ; 60(12): 1642-1654, 2020 12.
Article in English | MEDLINE | ID: mdl-32666570

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.


Subject(s)
Orexin Receptor Antagonists/adverse effects , Orexin Receptor Antagonists/pharmacokinetics , Pyridines/adverse effects , Pyridines/pharmacokinetics , Pyrimidines/adverse effects , Pyrimidines/pharmacokinetics , Sleep Initiation and Maintenance Disorders/drug therapy , Administration, Oral , Adolescent , Adult , Aged , Aged, 80 and over , Area Under Curve , Clinical Trials as Topic , Drug Elimination Routes , Female , Humans , Male , Middle Aged , Orexin Receptor Antagonists/administration & dosage , Orexin Receptor Antagonists/blood , Pyridines/administration & dosage , Pyridines/blood , Pyrimidines/administration & dosage , Pyrimidines/blood , Young Adult
4.
J Clin Psychopharmacol ; 40(2): 157-166, 2020.
Article in English | MEDLINE | ID: mdl-32134851

ABSTRACT

PURPOSE/BACKGROUND: Daridorexant is a dual orexin receptor antagonist in development for the treatment of sleep disorders. Thus far, it has not yet been studied in Japanese subjects. Study objectives were to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), and safety of single- and multiple-dose administration of daridorexant in healthy Caucasian and Japanese subjects. METHODS/PROCEDURES: This was a double-blind, placebo-controlled, randomized study. Subjects received once-daily doses of daridorexant (25 or 50 mg) or placebo for 5 days. Pharmacokinetics and safety were investigated using standard assessments. To assess PD effects, a battery of tests (saccadic peak velocity, body sway, adaptive tracking performance, and visual analog scales for alertness, mood, and calmness), known to be sensitive to sleep-promoting drugs was used. FINDINGS/RESULTS: On day 1, PK variables were similar between Caucasian and Japanese subjects. On day 5, slight accumulation occurred in Japanese but not in Caucasian subjects, resulting in a higher maximum concentration (1403 vs 1006 ng/mL) and area under the curve (8256 vs 6306 ng·h/mL) at a dose of 50 mg, whereas values for time to maximum concentration and half-life were similar. Daridorexant dose-dependently reduced vigilance, attention, visuomotor coordination, and postural stability. Pharmacokinetic effects were detectable within 1 hour after drug administration and returned to baseline 4 to 8 hours postdose. Overall, Japanese showed slightly larger PD effects and reported more adverse events than Caucasians. The most frequently reported were somnolence, fatigue, and headache. Changes in other safety assessments were unremarkable. IMPLICATIONS/CONCLUSIONS: The PK, PD, and safety profile of daridorexant were similar in Japanese and Caucasian subjects.


Subject(s)
Asian People , Orexin Receptor Antagonists/pharmacology , Orexin Receptor Antagonists/pharmacokinetics , White People , Adult , Female , Humans , Male , Middle Aged , Orexin Receptor Antagonists/blood
5.
J Clin Pharmacol ; 60(7): 931-941, 2020 07.
Article in English | MEDLINE | ID: mdl-32035014

ABSTRACT

ACT-539313 is a potent and selective orexin-1 receptor antagonist. CYP3A is the major cytochrome P450 (CYP) enzyme involved in the metabolism and clearance of ACT-539313 in man. The main objective of this study was to investigate the effect of ACT-539313 on the pharmacokinetics of orally administered midazolam. Thereby, this single-center, open-label, fixed-sequence study investigated the CYP3A interaction potential of ACT-539313 following single- (on day 2) and repeated-dose (on day 11) twice-daily administration of 200 mg ACT-539313. Exposure to midazolam was higher during concomitant administration of single as well as after repeated doses of ACT-539313 over 10 days compared to midazolam alone (day 1). In the presence of ACT-539313, the geometric mean ratio of the maximum plasma concentration and the area under the plasma concentration-time curve from time 0 to 24 hours increased by 1.18- and 1.79-fold on day 2, and by 2.13- and 4.54-fold on day 11, respectively. A similar outcome was also shown in the additionally evaluated urinary 6ß-hydroxycortisol/cortisol ratio (6ß-CR), as the geometric mean ratio of the 6ß-CR showed a decrease to 0.78 on day 2 and to 0.61 on day 11. The most commonly reported adverse events (AEs) included somnolence and headache. All AEs were transient and of mild intensity. No treatment-related effects on vital signs, clinical laboratory, and electrocardiogram were observed. In summary, the observed corresponding decrease of both the validated, exogenous (midazolam/1-hydroxymidazolam ratio) and a frequently used endogenous (6ß-CR) marker of CYP3A activity is indicative of CYP3A inhibition occurring after ACT-539313 treatment.


Subject(s)
Cytochrome P-450 CYP3A Inhibitors/pharmacokinetics , Cytochrome P-450 CYP3A/metabolism , Midazolam/pharmacokinetics , Orexin Receptor Antagonists/pharmacokinetics , Orexin Receptors/metabolism , Adult , Area Under Curve , Biomarkers/blood , Cytochrome P-450 CYP3A/drug effects , Cytochrome P-450 CYP3A Inhibitors/administration & dosage , Cytochrome P-450 CYP3A Inhibitors/adverse effects , Cytochrome P-450 CYP3A Inhibitors/blood , Drug Administration Schedule , Drug Interactions , Healthy Volunteers , Humans , Hydrocortisone/analogs & derivatives , Hydrocortisone/urine , Male , Midazolam/administration & dosage , Midazolam/adverse effects , Midazolam/analogs & derivatives , Midazolam/blood , Middle Aged , Orexin Receptor Antagonists/administration & dosage , Orexin Receptor Antagonists/adverse effects , Orexin Receptor Antagonists/blood , Orexin Receptors/drug effects , Young Adult
6.
Clin Pharmacol Ther ; 104(5): 1022-1029, 2018 11.
Article in English | MEDLINE | ID: mdl-29446069

ABSTRACT

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.


Subject(s)
Imidazoles/administration & dosage , Orexin Receptor Antagonists/administration & dosage , Pyrrolidines/administration & dosage , Sleep Aids, Pharmaceutical/administration & dosage , Wakefulness/drug effects , Administration, Intravenous , Administration, Oral , Adolescent , Adult , Biological Availability , Carbon Radioisotopes , Dose-Response Relationship, Drug , Double-Blind Method , Half-Life , Healthy Volunteers , Humans , Imidazoles/adverse effects , Imidazoles/blood , Imidazoles/pharmacokinetics , Isotope Labeling , Male , Metabolic Clearance Rate , Netherlands , Orexin Receptor Antagonists/adverse effects , Orexin Receptor Antagonists/blood , Orexin Receptor Antagonists/pharmacokinetics , Pyrrolidines/adverse effects , Pyrrolidines/blood , Pyrrolidines/pharmacokinetics , Sleep Aids, Pharmaceutical/adverse effects , Sleep Aids, Pharmaceutical/blood , Sleep Aids, Pharmaceutical/pharmacokinetics , Young Adult
7.
J Clin Pharmacol ; 55(10): 1093-100, 2015 Oct.
Article in English | MEDLINE | ID: mdl-25903940

ABSTRACT

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.


Subject(s)
Azepines/pharmacology , Orexin Receptor Antagonists/pharmacology , Respiration/drug effects , Sleep Aids, Pharmaceutical/pharmacology , Triazoles/pharmacology , Adult , Azepines/adverse effects , Azepines/blood , Azepines/pharmacokinetics , Cross-Over Studies , Double-Blind Method , Female , Healthy Volunteers , Humans , Male , Middle Aged , Orexin Receptor Antagonists/adverse effects , Orexin Receptor Antagonists/blood , Orexin Receptor Antagonists/pharmacokinetics , Oximetry , Oxygen/metabolism , Polysomnography , Sleep Aids, Pharmaceutical/adverse effects , Sleep Aids, Pharmaceutical/blood , Sleep Aids, Pharmaceutical/pharmacokinetics , Triazoles/adverse effects , Triazoles/blood , Triazoles/pharmacokinetics
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