PT  - JOURNAL ARTICLE
AU  - Alexander Treiber
AU  - Ruben de Kanter
AU  - Catherine Roch
AU  - John Gatfield
AU  - Christoph Boss
AU  - Markus von Raumer
AU  - Benno Schindelholz
AU  - Clemens Muehlan
AU  - Joop van Gerven
AU  - Francois Jenck
TI  - The Use of Physiology-Based Pharmacokinetic and Pharmacodynamic Modeling in the Discovery of the Dual Orexin Receptor Antagonist ACT-541468
AID  - 10.1124/jpet.117.241596
DP  - 2017 Sep 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 489--503
VI  - 362
IP  - 3
4099  - http://jpet.aspetjournals.org/content/362/3/489.short
4100  - http://jpet.aspetjournals.org/content/362/3/489.full
SO  - J Pharmacol Exp Ther2017 Sep 01; 362
AB  - 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 (OX1 and OX2) 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 OX2 receptor occupancy in brain. An active ACT-541468 dose of 25 mg was estimated on the basis of OX2 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.