Effect of gastric pH and of a moderate CYP3A4 inducer on the pharmacokinetics of daridorexant, a dual orexin receptor antagonist.

AIMS: Daridorexant is a dual orexin receptor antagonist developed for the treatment of insomnia. The solubility of daridorexant is pH-dependent and daridorexant has been shown to be a sensitive CYP3A4 substrate when co-administered with moderate CYP3A4 inhibitors. The purpose of this study was to assess the effect of an increased gastric pH on daridorexant pharmacokinetics (PK) and the extent of interaction when daridorexant is co-administered with a moderate CYP3A4 inducer. METHODS: In this prospective, single-centre, randomized, open-label study, 24 male subjects consecutively received four treatments, i.e., daridorexant 50 mg single dose; famotidine 40 mg single dose + daridorexant 50 mg single dose; efavirenz 600 mg once a day (o.d.) for 10 days; and daridorexant 50 mg single dose + efavirenz 600 mg o.d. for 2 days. Plasma PK parameters of daridorexant were derived by noncompartmental analysis. Standard safety and tolerability evaluations were analysed descriptively. RESULTS: When daridorexant administration was preceded by administration of famotidine, daridorexant Cmax decreased by 39%, geometric means ratio (GMR) (90% confidence interval [90% CI]): 0.61 (0.50, 0.73). AUC0-∞ remained unchanged. In the presence of steady-state efavirenz, daridorexant Cmax , AUC0-∞ and t½ decreased by approximately 35% (GMR [90% CI]): 0.65 (0.54, 0.78), 61% (0.39 (0.348, 0.44), and 35% (0.65 (0.58, 0.73), respectively. tmax remained unaffected. All treatments containing daridorexant were well tolerated. CONCLUSION: Daridorexant 50 mg can be administered concomitantly with gastric pH modifiers or with moderate CYP3A4 inducers without dose adaptation based on efficacy observed at lower doses in Phase 3 studies.

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.

First-in-human study with ACT-1014-6470, a novel oral complement factor 5a receptor 1 (C5aR1) antagonist, supported by pharmacokinetic predictions from animals to patients.

Aberrantly controlled activation of the complement system contributes to inflammatory diseases. Safety, tolerability, and pharmacokinetics of single-ascending doses of ACT-1014-6470, a novel orally available complement factor 5a receptor 1 antagonist, were assessed in a randomized, double-blind, placebo-controlled Phase 1 study. Six ACT-1014-6470 doses (0.5-200 mg) were selected after predictions from a Complex Dedrick plot. In each group, ACT-1014-6470 or matching placebo was administered to six and two healthy male individuals under fed conditions, respectively, including a cross-over part with 10 mg administered also under fasted conditions. Pharmacokinetic blood sampling and safety assessments (adverse events, clinical laboratory, vital signs, 12-lead electrocardiogram, and QT telemetry) were performed. ACT-1014-6470 was absorbed with a time to maximum plasma concentration (tmax ) of 3 h across dose levels and eliminated with a terminal half-life of 30-46 h at doses ≥ 2.5 mg. Exposure increased approximately dose proportionally. Under fed compared to fasted conditions, ACT-1014-6470 exposure was 2.2-fold higher and tmax delayed by 1.5 h. Pharmacokinetic modelling predicted that twice-daily oral administration is warranted in a subsequent multiple-dose study. No clinically relevant findings were observed in safety assessments. ACT-1014-6470 was well tolerated at all doses and could provide a novel therapy with more patient-friendly administration route compared to biologicals.

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.

Effect of Macitentan on the Pharmacokinetics of the Breast Cancer Resistance Protein Substrates, Rosuvastatin and Riociguat, in Healthy Male Subjects.

BACKGROUND: Macitentan is a clinically approved endothelin receptor antagonist for the treatment of pulmonary arterial hypertension (PAH). Increasing use of combination drug therapy in PAH means that it is important to recognize potential drug-drug interactions (DDIs) that could affect the efficacy and safety of macitentan in patients with PAH. OBJECTIVE: Two Phase 1 studies were conducted to investigate the effect of macitentan at steady-state on the pharmacokinetics of the breast cancer resistance protein (BCRP) substrates, rosuvastatin and riociguat in healthy male subjects. Another objective was to determine the safety and tolerability of concomitant administration of rosuvastatin or riociguat with macitentan. METHODS: Healthy male subjects received a single oral dose of rosuvastatin 10 mg (n = 20) or riociguat 1 mg (n = 20) on Day 1 (reference treatment). A loading oral dose of macitentan 30 mg was administered on Day 5 followed by macitentan 10 mg once-daily from Day 6 to Day 15 (riociguat study) or Day 6 to Day 16 (rosuvastatin study). A concomitant oral dose of rosuvastatin 10 mg or riociguat 1 mg was administered on Day 10 (test treatment). Pharmacokinetics were evaluated for 96 h after treatment on Day 1 and for 144 h (riociguat study) or 168 h (rosuvastatin study) after treatment on Day 10. To compare the reference and test treatments, the geometric mean ratio was calculated for the maximum plasma concentration (Cmax), the area under the plasma concentration-time curve (AUC) from zero (pre-dose) to time of the last measured concentration above the limit of quantification (AUC0-t), the AUC from zero to infinity (AUC0-∞) and the terminal elimination half-life (t½) of rosuvastatin, riociguat and riociguat's metabolite, M1. The difference in the time to reach maximum plasma concentration (tmax) was determined by the Wilcoxon test. Trough levels of macitentan and its metabolite, ACT-132577, were measured and safety was monitored throughout. RESULTS: Ninety percent confidence intervals of the geometric mean ratios were within the bioequivalence criteria of 0.80-1.25. There was no significant difference between test and reference tmax. Rosuvastatin or riociguat did not affect the steady-state concentrations of macitentan and ACT-132577. The adverse event profile was consistent with the known safety profiles of the drugs. CONCLUSIONS: Macitentan 10 mg did not affect the pharmacokinetics of BCRP substrates, rosuvastatin or riociguat in healthy male subjects. EudraCT numbers: 2017-003095-31 and 2017-003502-41.

Brain penetration of local anaesthetics in the rat: Implications for experimental neuroscience.

Multiple experimental neuroscience techniques rely on the use of general anaesthesia to minimize the discomfort associated to animal restraint and to achieve a more effective control of relevant physiological parameters. In order to minimise potential interference on brain neuronal activity, such studies are typically conducted at low anaesthetic doses. This practice is often coupled to peripheral infiltration of local anaesthetics to provide supplementary analgesia and prevent sub-threshold activation of pain pathways that may confound central measurements of brain function. However, little is known of the effect of peripheral anaesthesia on central measurements of brain activity in small laboratory animal species. In order to begin to address this question, we measured total and free brain exposure of five different local anaesthetics following subcutaneous infiltration of analgesic doses in a surgical protocol widely used in rodent neuroimaging and electrophysiology studies. Notably, all the anaesthetics exhibited detectable total and free brain concentrations at all the time points examined. Lidocaine and mepivacaine showed the highest free brain exposures (>525 ng/g), followed by bupivacaine and ropivacaine (>70 ng/g). The ester-type local anaesthetic tetracaine produced the lowest free brain exposure (<8.6 ng/g). Our data suggest that peripheral administration of local anaesthetics in small laboratory animals could result in pharmacologically active brain exposures that might influence and confound central measurements of brain function. The use of the ester-type anaesthetic tetracaine produced considerably lower brain exposure, and may represent a viable experimental option when local anaesthesia is required.

The relationship between lamotrigine concentration and change in resting motor threshold in a rodent model of motor cortex stimulation.

SUMMARY: The anticonvulsant sodium channel blocker lamotrigine (LTG) increases resting motor threshold (RMT) measured using transcranial magnetic stimulation (TMS) of the motor cortex in humans. However, studies suggest a weak relationship between LTG plasma concentration and increase in RMT. This undermines the possibility to use the technique to investigate the dose-efficacy relationship of lamotrigine or novel sodium channel blocking drugs. In order to investigate this relationship further, we have examined blood and brain concentrations of LTG in parallel with the drugs effects on RMT in a model in which electrical-stimulation is used to activate the motor cortex of propofol-anaesthetised rats. LTG (3-20 mg/kg s.c.) significantly increased RMT (P<0.001). There was a significant (P<0.01) positive correlation between LTG blood and brain concentration and increase in RMT; however correlation-coefficients were low (brain: r(2)=0.26 and blood r(2)=0.25), with evidence for non-responders, similar to human studies. The results show that the variation in RMT response is unlikely to be due to pharmacokinetic differences between subjects, and suggest that biological differences may underpin the variability. Understanding the source of this variability will be an important goal and, assuming some relationship between the effects of LTG on motor pathway excitability and the drugs anticonvulsant efficacy, could lead to a means to identify epilepsy patients that may be more likely to respond to treatment.