Daridorexant je duální antagonista orexinových receptorů typu 1 a typu 2 (OX1 a OX2), který byl nedávno FDA schválen pro léčbu dospělých trpících nespavostí. Bylo prokázáno, že je účinný při snižování příznaků nespavosti, zvyšování denní funkčnosti a zlepšování celkové kvality spánku. Daridorexant nabízí pacientům úlevu od nespavosti a zároveň se vyhýbá závažným vedlejším účinkům a problémům se závislostí, které mají tradiční léčebné postupy, jako jsou benzodiazepiny a sedativa. Zvýšená opatrnost a redukce dávkování je na místě u pacientů užívajících středně silné inhibitory CYP3A4. Kontraindikován je u pacientů užívajících silné inhibitory CYP3A4.

Daridorexant is a dual orexin type 1 and types 2 (OX1 and OX2) receptor antagonist that was recently approved by the US FDA for the treatment of adults suffering from insomnia. It was shown to be effective in reducing insomnia symptoms, increasing daytime functioning, and improving the overall quality of sleep. Daridorexant offers patients relief from insomnia while avoiding the severe side effects and dependency issues of traditional treatments like benzodiazepines and sedatives. Increased caution and dose reduction is appropriate in patients taking moderate CYP3A4 inhibitors. Daridorexant is contraindicated in patients taking strong CYP3A4 inhibitors.

• Klíčová slova
• daridorexant,
• MeSH
• antagonisté orexinového receptoru * aplikace a dávkování   farmakologie   terapeutické užití   MeSH
• imidazoly aplikace a dávkování   farmakologie   terapeutické užití   MeSH
• lékové interakce MeSH
• lidé MeSH
• multicentrické studie jako téma MeSH
• nežádoucí účinky léčiv MeSH
• poruchy iniciace a udržování spánku * farmakoterapie   MeSH
• randomizované kontrolované studie jako téma MeSH
• Check Tag
• lidé MeSH

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.

• MeSH
• dospělí MeSH
• imidazoly * MeSH
• lékové interakce MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• pyrrolidiny * MeSH
• rosuvastatin kalcium * MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND AND OBJECTIVE: The dual orexin receptor antagonist daridorexant was approved in 2022 for the treatment of insomnia at doses up to 50 mg once per night. This study aimed at investigating the effect of daridorexant 50 mg at steady state on the pharmacokinetics of dabigatran, the active moiety of dabigatran etexilate, and rosuvastatin, sensitive substrates of P-glycoprotein and breast cancer resistance protein, respectively. METHODS: This single-center, open-label, fixed-sequence study enrolled 24 healthy male subjects who were dosed orally with dabigatran etexilate 75 mg on days 1 (Treatment A1) and 9 (Treatment C1) as well as rosuvastatin 10 mg on days 3 (Treatment A2) and 11 (Treatment C2). On days 7-14, daridorexant (50 mg once daily) was administered. Blood samples for the pharmacokinetics of both substrates and the pharmacodynamics of dabigatran, i.e., two coagulation tests, were collected and safety assessments performed. Noncompartmental pharmacokinetic parameters and pharmacodynamic variables were evaluated with geometric mean ratios and 90% confidence intervals of Treatment C1/C2 versus A1/A2. RESULTS: Geometric mean ratios (90% confidence interval) of dabigatran maximum plasma concentration and area under the plasma concentration-time curve were 1.3 (1.0-1.7) and 1.4 (1.1-1.9), respectively, whereas the time to maximum plasma concentration and terminal half-life were comparable between treatments. Pharmacodynamic variables showed a similar pattern as dabigatran pharmacokinetics in both treatments. Rosuvastatin pharmacokinetics were unchanged upon concomitant daridorexant administration. All treatments were well tolerated. CONCLUSIONS: A mild inhibition of P-glycoprotein was observed after administration of daridorexant (50 mg once daily) at steady state, whereas breast cancer resistance protein was not affected. CLINICAL TRIAL REGISTRATION: NCT05480475; date of registration: 29 July, 2022.

• MeSH
• ABC transportér z rodiny G, člen 2 MeSH
• benzimidazoly MeSH
• dabigatran * škodlivé účinky   MeSH
• lidé MeSH
• nádorové proteiny MeSH
• nádory prsu * MeSH
• P-glykoprotein MeSH
• plocha pod křivkou MeSH
• pyridiny škodlivé účinky   MeSH
• rosuvastatin kalcium farmakologie   MeSH
• zdraví dobrovolníci pro lékařské studie MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

• Klíčová slova
• daridorexant, difelikefalin, tebentafusp,
• MeSH
• antagonisté CGRP receptorů farmakologie   terapeutické užití   MeSH
• dialýza ledvin MeSH
• lidé MeSH
• nádory uvey farmakoterapie   MeSH
• poruchy iniciace a udržování spánku farmakoterapie   MeSH
• pruritus farmakoterapie   MeSH
• rekombinantní fúzní proteiny farmakologie   terapeutické užití   MeSH
• schvalování léčiv * MeSH
• Check Tag
• lidé MeSH

Progress in the field of insomnia since 2017 necessitated this update of the European Insomnia Guideline. Recommendations for the diagnostic procedure for insomnia and its comorbidities are: clinical interview (encompassing sleep and medical history); the use of sleep questionnaires and diaries (and physical examination and additional measures where indicated) (A). Actigraphy is not recommended for the routine evaluation of insomnia (C), but may be useful for differential-diagnostic purposes (A). Polysomnography should be used to evaluate other sleep disorders if suspected (i.e. periodic limb movement disorder, sleep-related breathing disorders, etc.), treatment-resistant insomnia (A) and for other indications (B). Cognitive-behavioural therapy for insomnia is recommended as the first-line treatment for chronic insomnia in adults of any age (including patients with comorbidities), either applied in-person or digitally (A). When cognitive-behavioural therapy for insomnia is not sufficiently effective, a pharmacological intervention can be offered (A). Benzodiazepines (A), benzodiazepine receptor agonists (A), daridorexant (A) and low-dose sedating antidepressants (B) can be used for the short-term treatment of insomnia (≤ 4 weeks). Longer-term treatment with these substances may be initiated in some cases, considering advantages and disadvantages (B). Orexin receptor antagonists can be used for periods of up to 3 months or longer in some cases (A). Prolonged-release melatonin can be used for up to 3 months in patients ≥ 55 years (B). Antihistaminergic drugs, antipsychotics, fast-release melatonin, ramelteon and phytotherapeutics are not recommended for insomnia treatment (A). Light therapy and exercise interventions may be useful as adjunct therapies to cognitive-behavioural therapy for insomnia (B).

• MeSH
• antidepresiva terapeutické užití   MeSH
• benzodiazepiny terapeutické užití   MeSH
• dospělí MeSH
• lidé MeSH
• melatonin * terapeutické užití   farmakologie   MeSH
• poruchy iniciace a udržování spánku * terapie   farmakoterapie   MeSH
• spánek MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH