The orexin story and orexin receptor antagonists for the treatment of insomnia.

Insomnia is present in up to one third of the adult population worldwide, and it can present independently or with other medical conditions such as mental, metabolic, or cardiovascular diseases, which highlights the importance of treating this multifaceted disorder. Insomnia is associated with an abnormal state of hyperarousal (increased somatic, cognitive, and cortical activation) and orexin has been identified as a key promotor of arousal and vigilance. The current standards of care for the treatment of insomnia recommend non-pharmacological interventions (cognitive behavioural therapy) as first-line treatment and, if behavioural interventions are not effective or available, pharmacotherapy. In contrast to most sleep medications used for decades (benzodiazepines and 'Z-drugs'), the new orexin receptor antagonists do not modulate the activity of γ-aminobutyric acid receptors, the main inhibitory mechanism of the central nervous system. Instead, they temporarily block the orexin pathway, causing a different pattern of effects, e.g., less morning or next-day effects, motor dyscoordination, and cognitive impairment. The pharmacokinetic/pharmacodynamic properties of these drugs are the basis of the different characteristics explained in the package inserts, including the recommended starting dose. Orexin receptor antagonists seem to be devoid of any dependence and tolerance-inducing effects, rendering them a viable option for longer-term treatment. Safety studies did not show exacerbation of existing respiratory problems, but more real-world safety and pharmacovigilance experience is needed. This review provides an overview of the orexin history, the mechanism of action, the relation to insomnia, and key features of available drugs mediating orexin signalling.

Pharmacokinetics and Pharmacodynamics of the Dual Orexin Receptor Antagonist Daridorexant in Japanese and Caucasian Subjects.

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.

The dual orexin receptor antagonist daridorexant does not affect the pharmacokinetics of the BCRP substrate rosuvastatin.

Daridorexant is a dual orexin receptor antagonist in clinical development for the treatment of insomnia. Breast-cancer resistant protein (BCRP) is an efflux pump expressed in intestinal epithelium and hepatocytes, contributing to the absorption, distribution, and elimination of drugs and endogenous compounds. In vitro, daridorexant inhibits BCRP with an IC50 of 3.0 µmol/L. The BCRP substrate rosuvastatin is a cholesterol-lowering drug, recommended for clinical drug-drug interaction (DDI) studies. In order to exclude an inhibitory effect of daridorexant on BCRP, this single-centre, open-label, two-treatment Phase 1 study investigated the effect of daridorexant at steady state on the pharmacokinetics (PK) of single-dose rosuvastatin in 20 healthy male subjects. In addition, safety and tolerability were assessed. A single oral dose of 10 mg rosuvastatin on Day 1 was followed by 96 hours observation. Thereafter, 25 mg daridorexant was administered once daily (o.d.) on Days 5-8 and in combination with 10 mg rosuvastatin on Day 8. On Days 9-12, subjects received 25 mg daridorexant alone. PK sampling was performed up to 120 hours after treatment administration. The results showed that concomitant administration of 25 mg daridorexant o.d. at steady state did not affect the exposure parameters of rosuvastatin in a relevant way, as indicated by the ratios of geometric means (GMRs) ([rosuvastatin + daridorexant]/[rosuvastatin alone]) of 0.93 for both Cmax and AUC0-∞ . Administration of a single dose of 10 mg rosuvastatin, multiple doses of 25 mg daridorexant alone or in combination were well tolerated. Taken together, daridorexant and BCRP substrates can be safely co-administered.

The Use of Physiology-Based Pharmacokinetic and Pharmacodynamic Modeling in the Discovery of the Dual Orexin Receptor Antagonist ACT-541468.

The identification of new sleep drugs poses particular challenges in drug discovery owing to disease-specific requirements such as rapid onset of action, sleep maintenance throughout major parts of the night, and absence of residual next-day effects. Robust tools to estimate drug levels in human brain are therefore key for a successful discovery program. Animal models constitute an appropriate choice for drugs without species differences in receptor pharmacology or pharmacokinetics. Translation to man becomes more challenging when interspecies differences are prominent. This report describes the discovery of the dual orexin receptor 1 and 2 (OX1 and OX2) antagonist ACT-541468 out of a class of structurally related compounds, by use of physiology-based pharmacokinetic and pharmacodynamic (PBPK-PD) modeling applied early in drug discovery. Although all drug candidates exhibited similar target receptor potencies and efficacy in a rat sleep model, they exhibited large interspecies differences in key factors determining their pharmacokinetic profile. Human PK models were built on the basis of in vitro metabolism and physicochemical data and were then used to predict the time course of OX2 receptor occupancy in brain. An active ACT-541468 dose of 25 mg was estimated on the basis of OX2 receptor occupancy thresholds of about 65% derived from clinical data for two other orexin antagonists, almorexant and suvorexant. Modeling predictions for ACT-541468 in man were largely confirmed in a single-ascending dose trial in healthy subjects. PBPK-PD modeling applied early in drug discovery, therefore, has great potential to assist in the identification of drug molecules when specific pharmacokinetic and pharmacodynamic requirements need to be met.

Transfer of the Dual Orexin Receptor Antagonist Daridorexant into Breast Milk of Healthy Lactating Women.

The novel dual orexin receptor antagonist daridorexant was approved in 2022 for the treatment of adult patients with insomnia. The aim of this post-marketing study was to measure daridorexant and its major metabolites in breast milk and plasma of 10 healthy lactating subjects. This single-center, open-label study evaluated the transfer of the analytes into breast milk. A single dose of 50 mg was orally administered in the morning. Milk and blood samples were collected pre-dose and over a period of 72 h after dosing. The pharmacokinetics of daridorexant in milk and plasma were assessed including the cumulative amount and fraction of dose excreted, daily infant dose, and relative infant dose. Safety and tolerability were also investigated. All subjects completed the study. Daridorexant was rapidly absorbed into and distributed from plasma. Daridorexant and its major metabolites were measurable in breast milk. The cumulative total amount of daridorexant excreted over 72 h was 0.010 mg, which corresponds to 0.02% of the maternal dose. This corresponds to a mean daily infant dose of 0.009 mg/day and a relative infant dose of less than 0.22% over 24 h. The maternal safety profile was similar to that observed in previous studies. Low amounts of daridorexant and its metabolites were detected in the breast milk of healthy lactating women. Since the exposure and potential effects on the breastfed infant are unknown, a risk of somnolence or other depressant effects cannot be excluded.

Population pharmacokinetic modeling of daridorexant, a novel dual orexin receptor antagonist.

The analysis aimed at identifying subject-specific characteristics (covariates) influencing exposure to daridorexant and quantification of covariate effects to determine clinical relevance. Data from 13 phase I, two phase II, and two phase III studies were pooled to develop a population pharmacokinetic model describing daridorexant concentration over time. Covariate effects were quantified based on model predictions. A two-compartment model with dose-dependent bioavailability, absorption lag time, linear absorption, and nonlinear elimination described the data best. Statistically significant covariates were food status on absorption (lag time and rate constant), time of drug administration (morning, bedtime) on absorption rate constant, lean body weight on central volume of distribution and elimination, fat mass on peripheral volume of distribution and intercompartmental drug transfer, and age and alkaline phosphatase on elimination. Age, lean body weight, fat mass, and alkaline phosphatase influence exposure (area under the curve, time of maximum concentration after dose administration, maximum plasma concentration, and next-morning concentration) to a limited extent, that is, less than 20% difference from a typical subject. Morning administration is not relevant for daridorexant use by insomnia patients. The food effect with simultaneous intake of a high-fat, high-calorie food is an extreme-case scenario unlikely to occur in clinical practice. Body composition, alkaline phosphatase, and age showed clinically negligible effects on exposure to daridorexant. Lean body weight and fat mass described the pharmacokinetics of daridorexant better than other body size descriptors (body weight, height, body mass index), suggesting a convenient physiological alternative to reduce the number of covariates in population pharmacokinetic models. The results indicate that differences between subjects do not require dose adjustments.

Driving Performance after Bedtime Administration of Daridorexant, Assessed in a Sensitive Simulator.

Use of hypnotics is often associated with next-morning residual effects and a higher risk of motor vehicle accidents. Measuring next-morning effects on driving performance is therefore advised by regulatory agencies. Here, we examined driving performance following administration of daridorexant, a new dual orexin receptor antagonist developed to treat insomnia. Sixty healthy male and female subjects (50-79 years of age) were randomized in a placebo- and active-controlled, four-way cross-over study. Each subject received evening administration of daridorexant 50 and 100 mg, zopiclone 7.5 mg, and placebo, in separate treatment phases of 4 days. Simulated driving performance was assessed after initial (day 2) and repeated dosing (day 5), 9 hours postdose. Standard deviation of the lateral position (SDLP) was the main outcome. On both days, with zopiclone, SDLP increased significantly compared with placebo, which confirmed sensitivity of the simulator. With daridorexant, on day 2, the placebo-corrected mean (97.5% confidence interval) SDLP increased by 2.19 cm (0.46-3.93) and 4.43 cm (2.72-6.15) for 50 and 100 mg, respectively. On day 5, SDLP values for both daridorexant doses were significantly below the prespecified threshold of impairment (2.6 cm) and statistically not different from placebo. Daridorexant showed a lower self-rated driving quality and higher effort compared to placebo on day 2 but not on day 5. In non-insomnia subjects, daridorexant impaired simulated driving after initial but not after repeated dosing. Subjects should be cautioned about driving until they know how daridorexant affects them.

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.

Effect of Liver Cirrhosis on the Pharmacokinetics, Metabolism, and Tolerability of Daridorexant, A Novel Dual Orexin Receptor Antagonist.

BACKGROUND AND OBJECTIVE: Daridorexant is a dual orexin receptor antagonist in clinical development for insomnia. As daridorexant is cleared mainly via cytochrome P450 (CYP) 3A4, the effect of hepatic impairment on the pharmacokinetics (PK), metabolism, and tolerability of daridorexant was evaluated. Sleep disorders are common in patients with liver cirrhosis and, therefore, sleep-promoting drugs with a better tolerability than currently available would be preferable, a premise that dual orexin receptor antagonists may fulfill. METHODS: This was a single-dose, open-label, phase I study. Subjects with mild (Child-Pugh A, N = 8) or moderate (Child-Pugh B, N = 8) liver cirrhosis and matched healthy control subjects (N = 8) received 25 mg of daridorexant orally. Blood samples were collected for 72 h post-dose for PK assessments of daridorexant and three major metabolites. RESULTS: Compared with healthy subjects, patients showed a decrease in total daridorexant area under the plasma concentration-time curve from zero to infinity (AUC0-inf) and maximum plasma concentration with a geometric mean ratio (GMR, 90% confidence interval [CI]) of 0.51 (0.28-0.92) and 0.50 (0.35-0.72) in Child-Pugh A and 0.74 (0.39-1.41) and 0.42 (0.29-0.60) in Child-Pugh B patients, respectively. Furthermore, the median time to reach maximum plasma concentration was slightly delayed (1.0 h [90% CI 0.0-2.0] in Child-Pugh A patients and 0.5 h [90% CI 0.0-1.5] in Child-Pugh B patients), while for Child-Pugh B patients, a doubling in half-life was observed (GMR [90% CI]: 2.09 [1.32-3.30]). Considering the high plasma protein binding (> 99%) and a 1.9-fold to 2.3-fold increase in the unbound fraction in patients, the PK of unbound daridorexant was also assessed. Compared with healthy subjects, Child-Pugh B patients had a higher AUC0-inf (GMR [90% CI] 1.60 [0.93-2.73]), a lower apparent plasma clearance (GMR [90% CI] 0.63 [0.37-1.07]), and the same doubling in the half-life observed for total daridorexant, whereas maximum plasma concentration and apparent volume of distribution were not different. Unbound daridorexant PK in Child-Pugh A patients did not differ from healthy subjects. In addition, the metabolic ratios (parent to metabolite), i.e., a marker of CYP 3A4 activity, of the two most abundant daridorexant metabolites were higher in patients with liver cirrhosis compared with healthy subjects. All treatment-emergent adverse events were transient and of mild or moderate intensity and no other treatment-related effects were apparent. CONCLUSIONS: No safety issue of concern was detected following administration of 25 mg of daridorexant in the study population. Moderate liver cirrhosis causes impaired hepatic clearance of unbound daridorexant, which prolongs the half-life. A 25-mg dose of daridorexant should, therefore, not be exceeded in Child-Pugh B patients. A dose adjustment is not required in Child-Pugh A patients, while avoidance of daridorexant in patients with Child-Pugh C cirrhosis is recommended. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT03713242.

Impact of Daridorexant, a Dual Orexin Receptor Antagonist, on Cardiac Repolarization Following Bedtime Dosing: Results from a Thorough QT Study Using Concentration-QT Analysis.

BACKGROUND AND OBJECTIVE: Daridorexant is a new dual orexin receptor antagonist currently in late-stage clinical development for the treatment of insomnia. This randomized, double-blind, placebo-controlled, four-period crossover study investigated the effect of daridorexant at a therapeutic and supratherapeutic dose on QT interval duration. METHODS: Thirty-six healthy subjects received single oral doses of daridorexant (50 mg; 200 mg), moxifloxacin (400 mg; open label), and placebo. All treatments were administered at bedtime to mimic therapeutic practice. The primary analysis was based on linear mixed-effects concentration-QT modelling. Triplicate ECG data were extracted from Holter recordings at baseline and until 24 h post dosing at time points matching those for pharmacokinetic sampling. Plasma concentrations of daridorexant were determined over 24 h. RESULTS: Assay sensitivity was demonstrated based on mean baseline- and placebo-corrected QT interval using Fridericia's formula (ΔΔQTcF) > 5 ms following moxifloxacin administration (p < 0.01). Following daridorexant administration, mean (90% confidence interval, CI) ΔΔQTcF was 1.40 ms (0.48; 2.32 ms) and 1.84 ms (-0.12; 3.79 ms) at the Cmax of 747 ng/mL (50 mg dose) and 1809 ng/mL (200 mg dose), respectively, i.e., the upper bounds of the CIs were < 10 ms defined as threshold of regulatory concern. Lack of relevant QT prolongation was confirmed by secondary by-time point analysis and absence of relevant findings in the categorical outlier analysis. Daridorexant was safe and well tolerated and its pharmacokinetics were consistent with previous data. CONCLUSION: Daridorexant does not impair cardiac repolarization evidenced by absence of relevant QT prolongation at therapeutic and supratherapeutic doses. Clinical Trials Registration ID: NCT04250506.

Clinical pharmacology, efficacy, and safety of orexin receptor antagonists for the treatment of insomnia disorders.

INTRODUCTION: The last two decades have witnessed a rapid increase in the knowledge about the role of the orexin system, particularly in the regulation of wakefulness and arousal. Dual orexin receptor antagonists (DORAs) have been approved for the treatment of insomnia disorders (suvorexant, lemborexant) and drugs with a distinctive profile (daridorexant) or orexin-2 receptor selectivity (seltorexant) are in development. AREAS COVERED: This review discusses pharmacokinetics (PK), pharmacodynamics (PD), efficacy, and safety properties of orexin receptor antagonists (ORAs). EXPERT OPINION: In general, the drugs described have a similar effect on sleep characteristics although their pharmacokinetic variables differ. ORAs have the potential to revolutionize the pharmacological treatment of insomnia because they not only improve sleep, but, in addition, appear to have no dependence - and tolerance-inducing effects, which makes them suitable for long-term-treatment. The safety and tolerability profile of ORAs clearly differ from those of more traditional sleep-promoting drugs. Further research is needed to demonstrate benefits to patients suffering from insomnia disorder, e.g., with respect to improving not only sleep but also daytime functioning. In addition, ongoing and future research will show whether ORAs may have beneficial effects in patients with various psychiatric and neurodegenerative disorders, including Alzheimer's disease.

Pharmacological Interactions between the Dual Orexin Receptor Antagonist Daridorexant and Ethanol in a Double-Blind, Randomized, Placebo-Controlled, Double-Dummy, Four-Way Crossover Phase I Study in Healthy Subjects.

BACKGROUND: Daridorexant (ACT-541468) is a potent dual orexin receptor antagonist under development for the treatment of sleep disorders. Concomitant intake of ethanol and hypnotics has been shown to result in additive/supra-additive depression of the central nervous system, resulting in pronounced sedation. OBJECTIVE: The aim of this study was to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) interactions between ethanol and daridorexant. METHOD: This was a single-center, double-blind, placebo-controlled, randomized, four-way crossover study conducted in 19 healthy male/female subjects. Subjects received the following four treatments: ethanol with daridorexant, daridorexant alone, ethanol alone, and placebo. Daridorexant 50 mg and the matching placebo were administered as single oral tablets. Ethanol was infused intravenously and clamped at a level of 0.6 g/L for 5 h. The PK of ethanol and daridorexant were assessed and a battery of PD tests performed. RESULTS: Concomitant administration of ethanol prolonged the time to reach maximum plasma concentrations (tmax) of daridorexant (median difference 1.25 h). No other relevant PK interactions were observed. Coadministration with ethanol produced a numerically greater impairment on saccadic peak velocity, body sway, visual analog scale (VAS) alertness, VAS alcohol intoxication, smooth pursuit, and adaptive tracking compared with daridorexant alone. All treatments were generally well tolerated without serious adverse events (AEs). The most commonly reported treatment-emergent AEs following coadministration of daridorexant and ethanol included somnolence, headache, fatigue, sudden onset of sleep, and dizziness. CONCLUSIONS: Apart from a shift in tmax, no relevant changes in PK parameters were observed following coadministration of daridorexant and ethanol. The coadministration led to reinforced drug actions that were, at most, indicative of infra-additive effects on certain PD markers. Patients will be advised not to consume ethanol with daridorexant. CLINICAL TRIALS REGISTRATION NUMBER: NCT03609775 (ClinicalTrials.gov Identifier).

Clinical pharmacology of the dual orexin receptor antagonist ACT-541468 in elderly subjects: Exploration of pharmacokinetics, pharmacodynamics and tolerability following single-dose morning and repeated-dose evening administration.

BACKGROUND: The dual orexin receptor antagonist ACT-541468 showed sedative pharmacodynamic effects during initial clinical testing in adult subjects. The present study explored pharmacokinetics, pharmacodynamics and tolerability in healthy elderly subjects. METHODS: Double-blind, placebo-controlled, randomised, single-ascending dose study in 24 male/female elderly (65-80 years, 5, 15 and 25 mg in the morning, 6/2 active/placebo per group). Additionally, 10 subjects (8/2 active/placebo) received 25 mg for 7 days in the evening. Pharmacokinetics, pharmacodynamics (saccadic peak velocity, adaptive tracking, body sway, visual analogue scales according to Bowdle and Bond and Lader, Karolinska Sleepiness Scale) and tolerability were assessed. In particular, pharmacodynamics results are to be interpreted exploratorily. RESULTS: Absorption was quick with a median time to maximum concentration of ∼ 1.0 h. The mean elimination half-life was 8.5-9.8 h, the area under the curve and the maximum plasma concentration increased proportionally with dose. Following repeated evening administration of 25 mg, minimal accumulation was observed. There were no pharmacodynamic effects at 5 mg. At 15 mg, saccadic peak velocity (degree/s; SD) was reduced (69; 38), while other variables showed no effects. At 25 mg, effects on all objective pharmacodynamic parameters were observed. At 8-12 h post-dose, there were no differences to placebo and no next-day effects on pharmacodynamic variables after evening administration. Elderly subjects reported fewer adverse events compared to adults in previous studies. CONCLUSION: ACT-541468 in elderly subjects was well tolerated and pharmacokinetics and pharmacodynamics are compatible with a drug for the treatment of insomnia. Clinicaltrials.gov: NCT02571855.

Multiple-dose clinical pharmacology of ACT-541468, a novel dual orexin receptor antagonist, following repeated-dose morning and evening administration.

ACT-541468 is a dual orexin receptor antagonist with sleep-promoting effects in humans. Following entry-into-humans, its pharmacokinetics (PK) including dose-proportionality and accumulation, pharmacodynamics (PD), safety, and tolerability following multiple-ascending oral dose (MAD) administration in the morning, and next-day residual effects after repeated evening administration were investigated in a double-blind, placebo-controlled, randomized study. 31 healthy male and female subjects in 3 dose-groups (10, 25, and 75 mg) received study drug in the morning for 5 days (MAD part), and 20 healthy subjects received 25 mg in the evening for 1 week (evening part). PK, PD (saccadic peak velocity (SPV), adaptive tracking, body sway, Bond and Lader visual analogue scales (VAS), Karolinska Sleepiness Scale (KSS), VAS Bowdle for assessment of psychedelic effects), Digit Symbol Substitution Test (DSST), and Simple Reaction Time Test (SRTT), safety, and tolerability were assessed. ACT-541468 was absorbed with a median tmax of 1.0-2.0 h across the 3 dose groups. The geometric mean elimination half-life (t½) on Day 5 was between 5.6 and 8.5 h, and the exposure (area under the curve (AUC)) showed dose proportionality. No accumulation and no influence of sex on the multiple-dose PK parameters of ACT-541468 was observed. No effects were observed at 10 mg. Administration of 25 and 75 mg during the day showed clear dose-dependent effects on the PD parameters, while next-day effects were absent after evening administration of 25 mg. The drug was safe and well tolerated. In conclusion, multiple-dose PK/PD of ACT-541468 were compatible with a drug designated to treat insomnia.

Metabolism of the Dual Orexin Receptor Antagonist ACT-541468, Based on Microtracer/ Accelerator Mass Spectrometry.

BACKGROUND: As part of an integrated and innovative approach to accelerate the clinical development of the dual receptor antagonist ACT-541468, 6 healthy subjects in one cohort in a first-in-humans (FIH) study received an oral dose of 50 mg non-labeled ACT-541468 together with a microtracer amount of 250 nCi of 14C-labeled ACT- 541468 to investigate its absorption, distribution, metabolism, and excretion (ADME). METHODS: Using accelerator mass spectrometry (AMS), radiochromatograms were constructed for fractionated plasma, urine, and feces samples. Subsequently, the structures of the metabolites were elucidated using high performance liquid chromatography (HPLC) coupled with high resolution mass spectrometry. RESULTS: In total 77 metabolites have been identified of which 30, 28, and 60 were present in plasma, urine, and feces, respectively. In plasma, the major metabolites were the mono-oxidized benzylic alcohol M3, the ACT-541468 aldehyde M1, formed by further oxidation of M3 in the benzylic position, and the doubly oxidized M10, formed by (1) benzylic oxidation of M3 (loss of one molecule of water and one molecule of ammonia) and (2) additional loss of water from the oxidized pyrrolidine ring of M5. Transformation of the pyrrolidine to a 6-membered ring was detected. Metabolites that accounted for more than 5% of total radioactivity in excreta were M2, which is also formed by oxidation at the benzylic position, M4, formed by demethylation of the methoxy-group, M7 and A6, both formed by oxidation of M4, and M10, the only major metabolite detected in urine. CONCLUSION: In conclusion, ACT-541468 is extensively metabolized predominantly by oxidative transformations.

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.