The Use of Physiology-Based Pharmacokinetic and Pharmacodynamic Modeling in the Discovery of the Dual Orexin Receptor Antagonist ACT-541468

Abstract

The identification of new sleep drugs poses particular challenges in drug discovery owing to disease-specific requirements such as rapid onset of action, sleep maintenance throughout major parts of the night, and absence of residual next-day effects. Robust tools to estimate drug levels in human brain are therefore key for a successful discovery program. Animal models constitute an appropriate choice for drugs without species differences in receptor pharmacology or pharmacokinetics. Translation to man becomes more challenging when interspecies differences are prominent. This report describes the discovery of the dual orexin receptor 1 and 2 (OX and OX) antagonist ACT-541468 out of a class of structurally related compounds, by use of physiology-based pharmacokinetic and pharmacodynamic (PBPK-PD) modeling applied early in drug discovery. Although all drug candidates exhibited similar target receptor potencies and efficacy in a rat sleep model, they exhibited large interspecies differences in key factors determining their pharmacokinetic profile. Human PK models were built on the basis of in vitro metabolism and physicochemical data and were then used to predict the time course of OX receptor occupancy in brain. An active ACT-541468 dose of 25 mg was estimated on the basis of OX receptor occupancy thresholds of about 65% derived from clinical data for two other orexin antagonists, almorexant and suvorexant. Modeling predictions for ACT-541468 in man were largely confirmed in a single-ascending dose trial in healthy subjects. PBPK-PD modeling applied early in drug discovery, therefore, has great potential to assist in the identification of drug molecules when specific pharmacokinetic and pharmacodynamic requirements need to be met.

Daridorexant, a New Dual Orexin Receptor Antagonist to Treat Insomnia Disorder

“…The assessment of morning sleepiness showed no difference between any dose of daridorexant and placebo in terms of sleepiness the following day. This is assumed to be related to the short half‐life of daridorexant, as shown in phase 1 clinical trials in healthy subjects . The relatively short half‐life of daridorexant may also result in fewer residual effects.…”

“…This is assumed to be related to the short half-life of daridorexant, as shown in phase 1 clinical trials in healthy subjects. 11,14 The relatively short half-life of daridorexant may also result in fewer residual effects. In addition, daridorexant, in common with all DORAs, is designed to improve the quality of sleep, so an absence of next-morning residual effects would not be unexpected and would support the data generated showing objective improvement.…”

“…Human simulations of daridorexant suggested high and rapid peak orexin receptor occupancy and fast decline in receptor occupancy at a dose of 25mg. 11 Verifying model predictions, clinical studies in young and elderly healthy subjects who received daridorexant at doses ranging from 5 to 200mg showed a favorable safety profile. 12,13 The half-life was around 6 hours, and maximum plasma concentration occurred between 0.8 and 2 hours postdosing.…”

“…It was selected based on physiology‐based pharmacokinetic (PK) and pharmacodynamic (PD) modeling of 20 structural analogs out of >25,000 molecules synthesized. Human simulations of daridorexant suggested high and rapid peak orexin receptor occupancy and fast decline in receptor occupancy at a dose of 25mg …”

From Oxadiazole to Triazole Analogues: Optimization toward a Dual Orexin Receptor Antagonist with Improved in vivo Efficacy in Dogs

“…Suvorexant, developed by Merck is on the market since 2014 and no other orexin receptor antagonist had been approved by the FDA since. Intense research led to compounds currently investigated in late stage clinical trials for the treatment of insomnia, e. g. lemborexant ( 2 ) from Eisai or daridorexant ( 3 ) from Idorsia, both DORA's inhibiting orexin 1 and orexin 2 receptors (OX 1 R and OX 2 R, respectively). Seltorexant ( 4 ), a selective OX 2 R antagonist co‐developed by Janssen and Minerva Neurosciences is as well in clinical development for the treatment of insomnia .…”