Effect of Daridorexant on the Pharmacokinetics of Midazolam, and on the Pharmacokinetics and Pharmacodynamics of Warfarin in Healthy Male Subjects.

BACKGROUND AND OBJECTIVES: Daridorexant, a dual orexin receptor antagonist was recently approved for the treatment of insomnia at doses up to 50 mg once per night. This study investigated the effect of single-dose and multiple-dose daridorexant 50 mg at steady state on the pharmacokinetics (PK) of the cytochrome P450 (CYP) 3A4-sensitive substrate midazolam, and the effect of single-dose daridorexant 50 mg on the PK and pharmacodynamics (PD) of the CYP2C9-sensitive substrate warfarin. METHODS: In this prospective, single-center, open-label, fixed-sequence, phase I, drug-drug interaction study, 18 healthy male subjects sequentially received Treatment A, B, and C in three periods. Treatment A consisted of a single oral concomitant administration of midazolam 2 mg and warfarin 25 mg on day 1 of the first period. Treatment B consisted of one oral administration of daridorexant 50 mg followed 1 h later by a single oral dose of midazolam 2 mg concomitantly with a single oral dose of warfarin 25 mg on day 1 and a once-daily oral administration of daridorexant 50 mg for 6 days of the second period. Treatment C consisted of a single oral administration of daridorexant 50 mg at steady state followed 1 h later by a single oral administration of midazolam 2 mg on day 1 of the third period. Blood samples were assessed for midazolam and S-warfarin PK, and PD (international normalized ratio and factor VII). Noncompartmental  PK parameters and PD variables were evaluated with geometric mean ratios and 90% confidence intervals of Treatment B/A versus C/A for midazolam, and treatment B/A for warfarin. Safety and tolerability of each treatment were also assessed. RESULTS: Midazolam maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from 0 to 24 h (AUC0-24) were 1.13- and 1.42-fold higher, respectively, after single-dose administration of daridorexant 50 mg compared to administration of midazolam alone, while Cmax and AUC0-24 were 1.12- and 1.35-fold higher, respectively, after administration of daridorexant 50 mg once daily at steady state. Terminal half-life and time to maximum plasma concentration were comparable between treatments. Daridorexant had no influence on the PK and PD of warfarin. All treatments were safe and well tolerated. CONCLUSIONS: Daridorexant at 50 mg is classified as a weak CYP3A4 inhibitor after single- and multiple-dose administration once daily at steady state. Daridorexant 50 mg did not induce CYP3A4 activity or inhibit CYP2C9 activity. CLINICAL TRIAL REGISTRATION: This trial (NCT05480488) was registered on 29 July, 2022.

Intra-CA1 injection of orexin receptors antagonism attenuates the stress-induced analgesia in a rat acute pain model.

Orexins or hypocretins are excitatory neuropeptides predominantly produced by neuronal clusters in the lateral hypothalamus. The orexinergic system's involvement in pain modulation makes it a candidate for pain control alternative to the opioid system. Moreover, orexin-1 and orexin -2 receptors (OX1r and OX2r, respectively) play a role in responsiveness to stressful stimuli. Some evidence indicates that the Cornu Ammonis 1 (CA1) region of the hippocampus potentially participates in the modulation of both pain and stress. In quest of better understanding the interaction between orexin receptors and stress-induced analgesia (SIA), The present study examined the involvement of OX1r and OX2r within the CA1 in response to acute pain after exposure to forced swim stress (FSS) for a 6-min period. Adult male Wistar rats received different doses of OX1r antagonist (SB334867; 1, 3, 10, and 30 nmol), OX2r antagonist (TCS OX2 29; 3, 10, 30 and 100 nmol), or vehicle (0.5 µl DMSO) through an implanted cannula. After that, animals individually experienced acute pain by performing the tail-flick test. Results indicated that FSS produces antinociceptive responses in the tail-flick test. Blockade of both orexin receptors within the CA1 region attenuated the analgesic effect of FSS. The antinociceptive effect of swim stress was prevented by lower doses of SB334867 than TCS OX2 29. These findings show that the orexinergic system might be partially involved in the SIA via the OX1 and OX2 receptors in the hippocampal CA1 region.

Persistent effects of the orexin-1 receptor antagonist SB-334867 on naloxone precipitated morphine withdrawal symptoms and nociceptive behaviors in morphine dependent rats.

AIM OF THE STUDY: In this study, we investigated the effect of long-term administration of orexin receptor 1 (OXR1) antagonist on naloxone-precipitated morphine withdrawal symptoms and nociceptive behaviors in morphine-dependent rats. MATERIALS AND METHODS: Wistar rats received subcutaneous (s.c.) injections of morphine (6, 16, 26, 36, 46, 56, and 66 mg/kg, 2 ml/kg) at an interval of 24 h for 7 days. In chronic groups, the OXR1 antagonist, SB-334867 (20 mg/kg, i.p.), or its vehicle, was injected repetitively from postnatal day 1 (PND1)-PND23 and then for the following seven days before each morphine injection. Meanwhile, in acute groups, SB-334867, or its vehicle, was administered before each morphine injection. In groups of rats that were designated for withdrawal experiments, naloxone (2.5 mg/kg, i.p.) was administered after the last injection of morphine. In the formalin-induced pain, the effect of OXR1 inhibition on the antinociceptive effects of morphine was measured by injecting formalin after the final morphine injection. RESULTS: Animals that received long-term SB-334867 administration before morphine injection demonstrated a significant reduction in chewing, defecation, diarrhea, grooming, teeth chattering, wet-dog shake, and writhing. Inhibiting OXR1 for a long time increased formalin-induced nociceptive behaviors in interphase and phase II of the formalin-induced pain. CONCLUSIONS: Our results indicated that the inhibition of OXR1 significantly reduces the development of morphine dependence and behavioral signs elicited by the administration of naloxone in morphine-dependent rats. Furthermore, the prolonged blockade of OXR1 might be involved in formalin-induced nociceptive behaviors.

Orexin receptors in the CA1 region of hippocampus modulate the stress-induced antinociceptive responses in an animal model of persistent inflammatory pain.

Stress activates multiple neural pathways and neurotransmitters that often suppress pain perception, the phenomenon called stress-induced analgesia (SIA). Orexin neurons from the lateral hypothalamus project to entire brain structures such as the hippocampus. The present study examined this hypothesis that orexinergic receptors in the CA1 region of the hippocampus may play a modulatory role in the development of SIA in formalin test as an animal model of persistent inflammatory pain. One hundred-two adult male Wistar rats were administered with intra-CA1 orexin-1 receptor (OX1r) antagonist, SB334867, at the doses of 3, 10, 30, and 100 nmol or TCS OX2 29 as orexin-2 receptor (OX2r) antagonist at the doses of 1, 3, 10, and 30 nmol. Five min later, rats were exposed to forced swim stress (FSS) for a 6-min period. Then, pain-related behaviors induced by formalin injection were measured at the 5-min blocks during a 60-min period of formalin test. The current study indicated that solely stress exposure elicits antinociception in the early and late phases of the formalin test. The FSS-induced analgesia was prevented by intra-CA1 administration of SB334867 or TCS OX2 29 during either phase of the formalin test. Moreover, the contribution of the OX2r in the mediation of analgesic effect of stress was more prominent than that of the OX1r during both phases of the formalin test. It is suggested that OX1r and OX2r in the CA1 region of the hippocampus are involved in stress-induced analgesia in the animal model of persistent inflammatory pain.

Role of hippocampal orexin receptors in antinociception elicited by chemical stimulation of the lateral hypothalamus in the tail-flick test.

The lateral hypothalamus (LH) orexinergic neurons project to numerous brain regions implicated in pain perception, including the CA1 part of the hippocampal formation. Moreover, the roles of orexin receptors (OXRs) in the CA1 in anti-analgesic consequences of the LH chemical stimulation by carbachol, muscarinic receptor agonist, in acute pain have not been clarified. The current research showed OXRs antagonist administration's effect in the CA1 on analgesia elicited by the LH chemical stimulation in a tail-flick test as an acute model of pain. The control groups, including vehicle-control groups, were given intra-LH administration of saline (0.5 µL), following intra-CA1 infusion of DMSO (12 %; 0.5 µL), and carbachol-control groups were treated with carbachol (250 nM/0.5 µL saline) into the LH following DMSO in the CA1. Treated groups received SB334867 (1, 3, 10, and 30 nM/0.5 µL DMSO) or TCS OX2 29 (0.1, 1, 10, and 20 nM/0.5 µL DMSO) as OX1R or OX2R antagonist, respectively, in the CA1 prior intra-LH administration of carbachol. After all injections, all rats underwent the tail-flick test over a 60-min time. Infusion of SB334867 or TCS OX2 29 in the CA1 impaired the analgesic consequences following chemical stimulation of the LH in acute pain. Meanwhile suppressive impact of the OX1R or OX2R antagonist on the analgesic impact of LH chemical stimulation was approximately identical. The current investigation provided a new document about the critical involvement of hippocampal orexinergic system in the modulatory role of the LH-CA1 path in pain perception.

Effects of benzodiazepine and orexin receptor antagonist on cognitive function revealed by auditory event-related potentials.

BACKGROUND: Cognitive decline after oral administration of sedatives, such as benzodiazepines, is a serious side effect. Suvorexant, an orexin receptor antagonist, has a favorable tolerability and a limited side-effect profile. AIM: The purpose of this study was to estimate the cognitive decline 1 day after oral medication with lormetazepam, a benzodiazepine, and suvorexant by comparing mismatch negativity (MMN) and P300 reflecting auditory discrimination function. METHODS: Sixty healthy subjects (42 males) were randomly assigned to three groups receiving suvorexant 20 mg, lormetazepam 2 mg, or placebo in this double-blind, randomized control study. Event-related potential recordings during an auditory oddball task and a digit symbol substitution test (DSST) were performed 1 day after oral administration. RESULTS: MMN, on the day after oral administration, was significantly attenuated in the lormetazepam group compared with the other two groups, but there was no difference between the suvorexant and placebo groups. No significant difference was found in P300 amplitudes and DSST scores among the three groups. CONCLUSION: These findings suggest that suvorexant, unlike benzodiazepine, is not associated with cognitive deficits, as revealed by MMN but not P300. This study shows a neurophysiological difference in the effects of suvorexant and benzodiazepine on cognitive function.

Pharmacokinetics of daridorexant, a dual orexin receptor antagonist, are not affected by renal impairment.

The aim of this study was to evaluate the impact of renal impairment on the pharmacokinetics (PKs), safety, and tolerability of daridorexant, a dual orexin receptor antagonist intended for the treatment of insomnia. A single-center, open-label study evaluated the PKs of daridorexant in patients with severe renal function impairment (SRFI; determined by creatinine clearance using the Cockcroft-Gault equation; N = 8) not on dialysis, and in matched control subjects (based on sex, age, and body weight; N = 7). A single oral dose of daridorexant 25 mg was orally administered in the morning. Blood samples were collected up to 72 h postdose for PK assessments of daridorexant. In patients with SRFI, maximum plasma concentrations (Cmax ; geometric mean ratio [GMR] and 90% confidence interval [CI]: 0.94 [0.60-1.46]), time to reach Cmax (Tmax ; median difference [90% CI] of -0.25 h [-0.75 to 0.25]), and half-life (GMR [90% CI] of 0.99 [0.66-1.48]), were virtually unchanged. Exposure (area under the plasma concentration-time profile) to daridorexant was slightly higher in patients with SRFI than in control subjects with the GMR (90% CI) being 1.16 (0.63-2.12). No safety issue of concern was detected as all adverse events were transient and of mild or moderate intensity, and no treatment-related effects on vital signs, clinical laboratory, or electrocardiogram variables were observed following daridorexant administration in patients with SRFI and control subjects. Based on these observations, PK alterations of daridorexant due to renal function impairment are not considered of clinical relevance and no dose adjustment is necessary in these patients.

Effects of Bedtime Dosing With Suvorexant and Zolpidem on Balance and Psychomotor Performance in Healthy Elderly Participants During the Night and in the Morning.

PURPOSE/BACKGROUND: This study was designed as an early assessment of the safety of the orexin receptor antagonist suvorexant, but also included exploratory assessments of balance and psychomotor performance that are the focus of this report. METHODS/PROCEDURES: This was a double-blind, randomized, 3-period, crossover, phase 1 study. Balance and psychomotor performance were evaluated during the night in 12 healthy elderly participants after bedtime administration of suvorexant 30 mg (a supratherapeutic dose), the GABAergic agonist zolpidem 5 mg (the recommended dose in the elderly), or placebo. Balance (body sway measured by platform stability) and psychomotor performance (measured by choice reaction time) were assessed predose and at 1.5, 4, and 8 hours postdose in each period. Memory (measured by word recall) was assessed predose and at 4 hours postdose. FINDINGS/RESULTS: At 1.5 hours after nighttime administration of each drug (the approximate time of their anticipated maximal plasma concentrations), both zolpidem and suvorexant increased body sway versus placebo, with a greater increase for zolpidem than suvorexant. Suvorexant increased choice reaction time compared with placebo or zolpidem at 1.5 hours. There were no treatment differences on body sway or choice reaction time at 4 or 8 hours, or on word recall at 4 hours. IMPLICATIONS/CONCLUSIONS: These exploratory data suggest that a 30-mg dose of suvorexant (supratherapeutic) and a 5-mg dose of zolpidem (recommended dose in the elderly) impaired balance at 1.5 hours in healthy elderly people, with potentially less impairment for suvorexant relative to zolpidem, but no treatment differences on body sway or psychomotor performance at 4 and 8 hours. Because of their exploratory nature, these findings and their clinical relevance, if any, require confirmation in a prospective study.

Effects of Lemborexant on the Pharmacokinetics of Oral Contraceptives: Results From a Phase 1 Drug-Drug Interaction Study in Healthy Females.

Lemborexant is a dual orexin receptor antagonist approved in multiple countries including the United States, Canada, and Japan for the treatment of insomnia in adults. As women of childbearing potential may be prescribed insomnia drugs, a drug-drug interaction study was conducted. This single-center, open-label, fixed-sequence study examined potential drug-drug interactions between lemborexant and an oral contraceptive (OC) in healthy females (18-44 years, n = 20). The purpose of this study was to determine the effect of lemborexant 10 mg (at steady state) on the pharmacokinetics of a single dose of OC (0.03 mg ethinyl estradiol and 1.5 mg norethindrone acetate), assess the effect of a single dose of OC on lemborexant pharmacokinetics, and evaluate safety and tolerability of lemborexant and OC coadministration. Ethinyl estradiol maximum plasma drug concentration was not altered by lemborexant coadministration; area under the curve from zero time to the last quantifiable concentration was slightly increased, by 13%. No clinically relevant effects on norethindrone acetate pharmacokinetics were observed. Coadministration of OC with lemborexant had no clinically relevant effect on the steady-state pharmacokinetics of lemborexant. Adverse events were consistent with the known safety profile. These results support the conclusion that lemborexant and OC can be coadministered without dose adjustment.

Central blockade of orexin type 1 receptors reduces naloxone induced activation of locus coeruleus neurons in morphine dependent rats.

Orexin neuropeptides are implicated in the expression of morphine dependence. Locus coeruleus (LC) nucleus is an important brain area involving in the development of withdrawal signs of morphine and contains high expression of orexin type 1 receptors (OX1Rs). Despite extensive considerations, effects of immediate inhibition of OX1Rs by a single dose administration of SB-334867 prior to the naloxone-induced activation of LC neurons remains unknown. Therefore, we examined the direct effects of OX1Rs acute blockade on the neuronal activity of the morphine-dependent rats which underwent naloxone administration. Adult male rats underwent subcutaneous administration of 10 mg/kg morphine (two times/day) for a ten-day period. On the last day of experiment, intra-cerebroventricular administration of 10 µg/µl antagonist of OX1Rs, SB-334867, was performed just before intra-peritoneal injection of 2 mg/kg naloxone. Thereafter, in vivo extracellular single unit recording was employed to evaluate the electrical activity of LC neuronal cells. The outcomes demonstrated that morphine tolerance developed following ten-day of injection. Then, naloxone administration causes hyperactivity of LC neuronal cells, whereas a single dose administration of SB-334867 prior to naloxone prevented the enhanced activity of neurons upon morphine withdrawal. Our findings indicate that increased response of LC neuronal cells to applied naloxone could be prevented by the acute inhibition of the OX1Rs just before the naloxone treatment.

Paraventricular thalamic nucleus plays a critical role in consolation and anxious behaviors of familiar observers exposed to surgery mice.

Background: Consolation behaviors toward the sick are common in humans. Anxiety in the relatives of the sick is also common. Anxiety can cause detrimental effects on multiple systems. However, our understanding on the neural mechanisms of these behaviors is limited because of the lack of small animal models. Methods: Five of 6- to 8-week-old CD-1 male mice were housed in a cage. Among them, 2 mice had right common artery exposure (surgery) and the rest were without surgery. Allo-grooming and performance in light and dark box and elevated plus maze tests of the mice were determined. Results: Mice without surgery had increased allo-grooming toward mice with surgery but decreased allo-grooming toward non-surgery intruders. This increased allo-grooming toward surgery mice was higher in familiar observers of surgery mice than that of mice that were not cage-mates of surgery mice before the surgery. Familiar observers developed anxious behavior after being with surgery mice. Surgery mice with familiar observers had less anxious behavior than surgery mice without interacting with familiar observers. Multiple brain regions including paraventricular thalamic nucleus (PVT) were activated in familiar observers. The activated cells in PVT contained orexin receptors. Injuring the neurons with ibotenic acid, antagonizing orexin signaling with an anti-orexin antibody or inhibiting neurons by chemogenetic approach in PVT abolished the consolation and anxious behaviors of familiar observers. Conclusions: Mice show consolation behavior toward the sick. This behavior attenuates the anxious behavior of surgery mice. The orexin signaling in the PVT neurons play a critical role in the consolation of familiar observers toward surgery mice and their anxious behavior. Considering that about 50 million patients have surgery annually in the United States, our study represents the initial attempt to understand neural mechanisms for consolation and anxiety of a large number of people.

Effect of severe renal impairment on pharmacokinetics, safety, and tolerability of lemborexant.

The primary aim of this study was to examine the effect of severe renal impairment (SRI) on the pharmacokinetics of lemborexant, a dual orexin receptor antagonist indicated for the treatment of insomnia. A phase 1 multicenter, single-dose, open-label, parallel-group study was conducted in subjects with SRI not requiring dialysis (estimated glomerular filtration rate 15-29 ml/min/1.73 m2 ; n = 8) compared with demographically matched healthy subjects with normal renal function (n = 8). Plasma levels of lemborexant and its metabolites were measured over 240 h following a single oral 10-mg dose administered in the morning. Relative to subjects with normal renal function, lemborexant maximum plasma concentration (Cmax ) was similar, whereas area under the plasma concentration-time curve from zero to time of last quantifiable concentration (AUC(0-t) ) and AUC from zero to infinity (AUC(0-inf) ) were about 1.5-fold higher in subjects with SRI. The geometric mean ratios (90% confidence interval) were 104.8 (77.4-142.0), 150.5 (113.2-200.3), and 149.8 (113.1-198.6) for Cmax , AUC(0-t) , and AUC(0-inf) , respectively. In both groups, the median lemborexant time to Cmax (tmax ) was 1 h, and the mean unbound fraction of lemborexant was ~7%. For the M4, M9, and M10 metabolites, Cmax was reduced ~20% and exposure (AUC(0-t) and AUC(0-inf) ) was ~1.4- to 1.5-fold higher in subjects with SRI versus healthy subjects; tmax was delayed ~1.5-2 h for M4 and M10. All treatment-emergent adverse events were mild or moderate. Lemborexant pharmacokinetics were not sufficiently altered to warrant a dose adjustment for subjects with renal impairment.

Physiologically-based pharmacokinetic modeling to predict drug interactions of lemborexant with CYP3A inhibitors.

Lemborexant, a recently approved dual orexin receptor antagonist for treatment of adults with insomnia, is eliminated primarily by cytochrome P450 (CYP)3A metabolism. The recommended dose of lemborexant is 5 mg once per night, with a maximum recommended dose of 10 mg once daily. A physiologically-based pharmacokinetic (PBPK) model for lemborexant was developed and applied to integrate data obtained from in vivo drug-drug interaction (DDI) assessments, and to further explore lemborexant interaction with CYP3A inhibitors and inducers. The model predictions were in good agreement with observed pharmacokinetic data and with DDI results from clinical studies with CYP3A inhibitors, itraconazole and fluconazole. The model further predicted that DDI effects of weak CYP3A inhibitors (fluoxetine and ranitidine) are weak, and effects of moderate inhibitors (erythromycin and verapamil) are moderate. Based on the PBPK simulations and clinical efficacy and safety data, the maximum daily recommended lemborexant dose when administered with weak CYP3A inhibitors is 5 mg; co-administration of moderate and strong inhibitors should be avoided except in countries where 2.5 mg has been approved.

Respiratory Safety of Lemborexant in Healthy Subjects: A Single-Dose, Randomized, Double-Blind, Placebo-Controlled, Crossover Study.

BACKGROUND AND OBJECTIVE: Lemborexant is a dual orexin receptor antagonist recently approved in the USA, Japan, and Canada for the treatment of adults with insomnia. Because some pharmacotherapy for insomnia causes respiratory depression, this study assessed the effects of lemborexant treatment on respiratory safety parameters. METHODS: This single-dose, randomized, double-blind, placebo-controlled, three-period crossover study enrolled healthy adult and elderly subjects (n = 17). Subjects were randomized to one of three treatment sequences, each consisting of three treatment periods in which they received a single dose of placebo, lemborexant 10 mg, or lemborexant 25 mg. Each treatment period was separated by a washout period of at least 14 days. Assessments included pharmacodynamic respiratory parameters (peripheral capillary oxygen saturation (SpO2) and apnea-hypopnea index (AHI)) and safety. RESULTS: There were no significant differences for either dose of lemborexant versus placebo in mean peripheral capillary oxygen saturation (SpO2; least squares mean (LSM) difference (95% confidence interval (CI)): lemborexant 10 mg, -0.36 (-0.78 to 0.07); lemborexant 25 mg, - 0.29 (- 0.72 to 0.14)) or AHI (LSM difference (95% CI): lemborexant 10 mg, 0.52 (- 1.72 to 2.76); lemborexant 25 mg, - 1.16 (- 3.40 to 1.08)) during sleep. Additionally, significant differences were not observed for the percentage of total sleep during which SpO2 was < 85% (LSM difference (95% CI): lemborexant 10 mg, 0.004 (- 0.058 to 0.067); lemborexant 25 mg, 0.044 (- 0.018 to 0.107)) or < 80% (LSM difference (95% CI): lemborexant 10 mg, 0.001 (- 0.002 to 0.005); lemborexant 25 mg, 0.002 (-0.001 to 0.006)) for either lemborexant dose versus placebo. There was also no significant difference for lemborexant 10 mg versus placebo, for which SpO2 was < 90% during total sleep time (LSM difference (95% CI): 0.185 (- 0.034 to 0.405)). CONCLUSION: Overall, lemborexant at recommended doses did not have a negative effect on mean SpO2 or AHI and was well tolerated in this cohort of healthy subjects.

Insomnia is a sleep disorder in which people have trouble falling asleep or staying asleep, or both. People can take prescription medicines to help improve sleep, but these drugs can have side effects including making breathing more difficult during sleep. We looked at a new medicine for insomnia, lemborexant, and with the aim of finding out how it affects breathing during sleep and if there were any side effects. A group of 17 healthy adult and elderly people took a normal or high dose of lemborexant or a placebo that did not contain active medicine. Researchers measured people's breathing while they slept. We found that lemborexant did not change the amount of oxygen in people's blood during sleep, and that lemborexant did not cause people to have shallow breathing or to have brief pauses in their breathing. People who took lemborexant reported few side effects and these were all mild. In this study, lemborexant was well tolerated in healthy adults and elderly people and did not make breathing more difficult during sleep.

Orexin Modulation of VTA Dopamine Neuron Activity: Relevance to Schizophrenia.

BACKGROUND: The hippocampus is a region consistently implicated in schizophrenia and has been advanced as a therapeutic target for positive, negative, and cognitive deficits associated with the disease. Recently, we reported that the paraventricular nucleus of the thalamus (PVT) works in concert with the ventral hippocampus to regulate dopamine system function; however, the PVT has yet to be investigated as target for the treatment of the disease. Given the dense expression of orexin receptors in the thalamus, we believe these to be a possible target for pharmacological regulation of PVT activity. METHODS: Here we used the methylazoxymethanol acetate (MAM) rodent model, which displays pathological alterations consistent with schizophrenia to determine whether orexin receptor blockade can restore ventral tegmental area dopamine system function. We measured dopamine neuron population activity, using in vivo electrophysiology, following administration of the dual orexin antagonist, TCS 1102 (both intraperitoneal and intracranial into the PVT in MAM- and saline-treated rats), and orexin A and B peptides (intracranial into the PVT in naïve rats). RESULTS: Aberrant dopamine system function in MAM-treated rats was normalized by the systemic administration of TCS 1102. To investigate the potential site of action, the orexin peptides A and B were administered directly into the PVT, where they significantly increased ventral tegmental area dopamine neuron population activity in control rats. In addition, the direct administration of TCS 1102 into the PVT reproduced the beneficial effects seen with the systemic administration in MAM-treated rats. CONCLUSION: Taken together, these data suggest the orexin system may represent a novel site of therapeutic intervention for psychosis via an action in the PVT.

Effect of the novel dual orexin receptor antagonist daridorexant on night-time respiratory function and sleep in patients with moderate chronic obstructive pulmonary disease.

In patients with chronic obstructive pulmonary disease (COPD), sleep is often fragmented while, conversely, the use of sleep medications is of concern in these patients due to potential impairment of nocturnal breathing. This randomised, double-blind, placebo-controlled, two-period crossover study was conducted to evaluate the effect of the new dual orexin receptor antagonist daridorexant on night-time respiratory function and sleep in patients with moderate COPD. In each period, the highest Phase-III dose of 50 mg daridorexant or placebo was administered once daily in the evening for 5 consecutive days. The primary endpoint was peripheral oxygen saturation (SpO2 ) during total sleep time (TST) after last dosing. Night-time respiratory function and sleep were further evaluated based on the apnea-hypopnea index (AHI), sleep duration, and objective sleep parameters. Pharmacokinetics, safety, and tolerability were also assessed. Primary endpoint analysis revealed no significant mean treatment difference (i.e. daridorexant - placebo) for SpO2 during TST as it was 0.18% (90% confidence interval: -0.21 to 0.57). There was also no difference from placebo for SpO2 during non-rapid eye movement (REM) and REM sleep at Night 5 and after first dosing. The AHI was slightly increased compared to placebo, but not to a clinically meaningful extent. In addition, daridorexant improved objective sleep parameters (i.e. prolonged TST, increased sleep efficiency, and decreased wake after sleep onset), reached expected plasma concentrations, and was safe and well tolerated. In conclusion, single and multiple doses of 50 mg daridorexant do not impair night-time respiratory function and improves sleep in patients with moderate COPD.

Blockade of orexin receptors in the ventral tegmental area reduced the extinction period of the lateral hypothalamic-induced conditioned place preference in rats.

The orexinergic connection between the lateral hypothalamus (LH) and the ventral tegmental area (VTA) is involved in modulating the reward circuit. The conditioned place preference (CPP) can be induced by microinjection of carbachol, a cholinergic agonist, into the LH. The current research was conducted to understand whether intra-VTA orexin receptors (OXRs) could influence the duration of the extinction period or maintenance of the intra-LH carbachol-induced CPP. To this end, the rats unilaterally received intra-LH carbachol (250 nM) within a 3-day conditioning period. Animals that have already passed the conditioning test were unilaterally administered by intra-VTA microinjection of SB334867, an OX1R antagonist, or TCS OX2 29, an OX2R antagonist during the extinction phase of the LH stimulation-induced CPP. For the first time, our data indicated that daily intra-VTA administration of either SB334867 (30 nM) or TCS OX2 29 (10 and 30 nM) during the extinction period decreased the maintenance of intra-LH carbachol-induced CPP. In conclusion, OXRs in the VTA play crucial roles in the maintenance of reward processes.

Evaluation of the CYP3A and CYP2B6 Drug-Drug Interaction Potential of Lemborexant.

Lemborexant is approved for treating insomnia and is under investigation for treating irregular sleep-wake rhythm disorder. Based on in vitro drug-drug interaction (DDI) characteristics, phase 1, open-label DDI studies were conducted to evaluate lemborexant's cytochrome P450 3A (CYP3A) and CYP2B6 interaction potential. Interactions between lemborexant 10 mg and strong and moderate CYP3A inhibitors (itraconazole and fluconazole), a strong CYP3A inducer (rifampin), and CYP3A (midazolam) and CYP2B6 substrates (bupropion) were evaluated. Coadministration of lemborexant with itraconazole or fluconazole resulted in 1.4- to 1.6-fold and 3.7- to 4-fold increases in lemborexant maximum observed concentration (Cmax ) and area under the concentration-time curve from zero time extrapolated to infinity (AUC0-inf ), respectively. Coadministration of lemborexant with rifampin resulted in >90% decreases in lemborexant Cmax and AUC0-inf . Midazolam exposure was not affected. Coadministration of lemborexant with bupropion resulted in 49.9% and 45.5% decreases in S-bupropion Cmax and AUC0-inf , respectively.Comparison of estimated exposures for patients in phase 3 trials who were/were not receiving concomitant weak CYP3A inhibitors substantiated the DDI pharmacokinetic findings. Lemborexant was generally well tolerated in the phase 1 studies. In summary, lemborexant does not affect the pharmacokinetics of CYP3A substrates and has potential to induce CYP2B6. Consistent with in vitro findings, moderate and strong CYP3A inhibitors and inducers affected the pharmacokinetics of lemborexant; hence, patients taking lemborexant 5 or 10 mg should avoid coadministration with moderate and strong CYP3A inhibitors and inducers.

Lack of residual morning effects of lemborexant treatment for insomnia: summary of findings across 9 clinical trials.

OBJECTIVES: Residual next-day effects of sleep-promoting drugs are common and an important safety issue. Lemborexant is a dual orexin receptor antagonist approved in the United States and Japan for treatment of insomnia in adults. We evaluated the potential of lemborexant for residual morning and next-day effects, including somnolence, based on lemborexant clinical study findings. METHODS: This paper reports findings from 9 lemborexant clinical studies that incorporated next-day assessments of residual drug effects, based on published findings and data on file. Results are reported for healthy subjects or subjects with insomnia disorder treated with lemborexant 5 mg/day or 10 mg/day, placebo, or active comparator before bedtime. Outcomes assessed included next-morning postural stability (body sway measured by ataxiameter), cognitive performance (Cognitive Performance Assessment Battery), impact on driving (standard deviation of lateral position during highway driving test), subjective sleepiness (sleep diary entries), and adverse events of somnolence. RESULTS: Change from baseline in postural stability the morning after lemborexant administration did not differ from placebo. Among 4 Cognitive Performance Assessment Battery measures, only power of attention declined significantly more with lemborexant treatment compared with placebo in 1 of 2 studies, whereas zolpidem differed from placebo on multiple measures. On the highway-driving test, lemborexant did not significantly impair driving performance versus placebo, however, zopiclone did differ. In large phase 3 trials, next-morning sleep diary ratings showed significantly greater alertness with lemborexant compared with placebo after up to 6 months of treatment. As expected, somnolence was the most common adverse event reported with lemborexant treatment. Somnolence was typically mild to moderate in severity and rarely caused discontinuation of study drug. CONCLUSION: Across 9 clinical studies, lemborexant did not substantially impair next-day functioning among healthy subjects and subjects with insomnia.

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.

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.