The orexin system plays a major role in the integration of metabolic and circadian influences that drive wakefulness. This paper describes initial Phase I trials of a novel dual orexin receptor antagonist SB-649868 that has demonstrated preclinical potential for treatment of sleep disorders. The trial designs included a single ascending dose escalation study (dose range: 10-80 mg in the fed and fasted states) and a multiple repeat dose study (dose range: 5-30 mg in the fed state) enrolling a total of 103 male volunteer subjects. SB-649868 was well tolerated at all doses in this study population, with mechanism-related adverse events (e.g. somnolence and fatigue) observed in a majority of subjects after 60 and 80 mg single doses. Although total drug exposure was similar in the fed and fasted states, the rate, but not the extent, of absorption increased in the fed state, resulting in an increased C(max). The typical estimated half-life of SB-649868 was 3-6 h - comparable with currently used hypnotic agents. Repeated administration of SB-649868 dose-dependently increased exposure to simvastatin (10 mg), suggesting CYP3A4 inhibition ranging from very mild (5 mg) to strong (30 mg). Evening dosing resulted in significant dose-dependent improvement in latency to persistent sleep, total sleep time and wake after sleep onset as measured by polysomnography. Next-morning testing did not detect evidence of residual cognitive effects. Results of these trials support further investigation of SB-649868 and other dual orexin receptor antagonists as potentially effective and well-tolerated treatments for patients with sleep disorders.

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The Highly Active Liquid Effluent and Storage plant at Sellafield, UK, currently uses three evaporators to reduce the volume of active liquor stored within the facility before being vitrified for long term storage. This liquor is highly corrosive and the lifetime of the evaporators is potentially limited by the corrosion loss from the heating elements, comprising an external jacket and a number of internal coils, all heated by low pressure steam. Inspection of the heating coils inside the evaporators is possible and measurement data is available of their thicknesses by depth at various inspection intervals. This inspection data has been combined with operational data and thermal models for the heating elements. Our theoretical understanding from laboratory measurements suggests that corrosion is related to temperature through an Arrhenius relationship. As such we have been able to develop a predictive model for the thickness profiles and remaining useful life of the uninspected components. This model is a non-linear mixed effects (multilevel) model and has undergone significant developmental work to account for a number of practical data issues. This paper will briefly outline the various components of the model, whilst discussing issues relevant to any statistical model such as complexities of data collection, approaches to handling correlated data, selecting appropriate model formulations and data transformations. The inclusion of uncertainties in prediction via Monte-Carlo simulation will also be discussed.