Summary: 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.

The orexin system is a key regulator of sleep and wakefulness. In a multicenter, double‐blind, randomized, placebo‐controlled, two‐way crossover study, 161 primary insomnia patients received either the dual orexin receptor antagonist almorexant, at 400, 200, 100, or 50 mg in consecutive stages, or placebo on treatment nights at 1‐week intervals. The primary end point was sleep efficiency (SE) measured by polysomnography; secondary end points were objective latency to persistent sleep (LPS), wake after sleep onset (WASO), safety, and tolerability. Dose‐dependent almorexant effects were observed on SE, LPS, and WASO. SE improved significantly after almorexant 400 mg vs. placebo (mean treatment effect 14.4%; P < 0.001). LPS (–18 min (P = 0.02)) and WASO (–54 min (P < 0.001)) decreased significantly at 400 mg vs. placebo. Adverse‐event incidence was dose‐related. Almorexant consistently and dose‐dependently improved sleep variables. The orexin system may offer a new treatment approach for primary insomnia. Clinical Pharmacology & Therapeutics (2012); 91 6, 975–985. doi:10.1038/clpt.2011.370

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 antagonist...

Pediatric aspects are nowadays integrated early in the development process of a new drug. The stronger enforcement to obtain pediatric information by the regulatory agencies in recent years resulted in an increased number of trials in children. Specific guidelines and requirements from, in particular, the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) form the regulatory framework. This review summarizes the regulatory requirements and strategies for pediatric drug development from an industry perspective. It covers pediatric study planning and conduct, considerations for first dose in children, appropriate sampling strategies, and different methods for data generation and analysis to generate knowledge about the pharmacokinetics (PK) and pharmacodynamics (PD) of a drug in children. The role of Modeling and Simulation (M&S) in pediatrics is highlighted—including the regulatory basis—and examples of the use of M&S are illustrated to support pediatric drug development.