Animal testing for suvorexant begin pre-clinically,with preliminary assessments typically based on the drug’s potential efficacyand overall tolerability. Initially known as compound 3 or MK-4503, receptoroccupancy measurements in the brains of rats showed suvorexant had promise as apotent dual orexin receptor antagonist, with a suggested receptor occupancygreater than 90% at 30 mg/kg/day.
Suvorexant pharmacokinetic properties alsoappeared favourable from the initial animal testing data and from this it waspredicted to be a moderate to low clearance compound with good bioavailabilityand a rapid onset of action in humans, going on the assumption that oxidativemetabolism would be the primary mode of elimination. Furthermore suvorexantappeared efficacious, inducing significant changes insleep architecture practically with increases in REM and delta sleep observedwith a corresponding decrease in active wake time when studied intelemetry-implanted rats (Cox et al., 2010). After suvorexant was shown to be well toleratedand potentially efficacious as a possible treatment for insomnia, furtherpre-clinical studies went on to examine in more detail the prospective effectsof suvorexant on a wider variety of animal species. In the studycarried out by Winrow et al., theeffect of suvorexant on sleep architecture was assessed in canine, monkey andrat species, all of which were surgically implanted with radio telemetricphysiologic monitors.
Sleep architecture was assessed by continuous monitoringof electroencephalogram (EEG) and electromyogram (EMG) readings during sleep oractive stage. The results of this study validated previous observations thatsuvorexant possessed a high affinity for both orexin receptors and moreoverdemonstrated its ability to induce considerable increases in non-REM and REMsleep in all preclinical species. These results were instrumental in supportingthe development of suvorexant as a novel therapeutic for insomnia movingforward into clinical studies (Winrow et al., 2011). Following multiple clinical trials proving it’sefficacy and safety for the treatment of insomnia suvorexant was subsequentlyapproved for distribution, however it is still being analysed in studiesinvolving animal testing. For example,in the development of new orexin receptor antagonist suvorexant was used as apositive control in the study on mice carried out by Betschart et al.
, as it was then known to be effectivein the treatment of insomnia. Aspredicted suvorexant induced a strong increase in REM sleepand non-REM sleep with REM accounting for much of the increase in total sleeptime. The test compound was also found to induce sleep but compared tosuvorexant the increase in total sleep time was mainly attributed to non-REMsleep (Betschart et al., 2013). More recently suvorexant has been assessed inanimals with the intention of possibly elucidating a potential new treatmentoption for type 2 diabetes.
In the study carried out by Tsuneki et al., sleepdisturbances were shown to be more common among diabetic mice as compared tonondiabetic control mice. Suvorexant administration was shown to amelioratethese disturbances by increasing REM and non-REM sleep times and decreasing theawake time in diabetic mice. As a result, glucose metabolism was also improvedin the mice as compared to vehicle control. Therefore not only has suvorexant shownto be effective in the treatment of insomnia but may also be a promisingtreatment for metabolic diseases associated with sleep disturbances, includingtype 2 diabetes (Tsuneki et al., 2016).