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

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 362; no. 3; pp. 489 - 503
• Main Authors: Treiber, Alexander, de Kanter, Ruben, Roch, Catherine, Gatfield, John, Boss, Christoph, von Raumer, Markus, Schindelholz, Benno, Muehlan, Clemens, van Gerven, Joop, Jenck, Francois
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2017
• Subjects: Animals; Brain - drug effects; Brain - physiology; CHO Cells; Cricetinae; Cricetulus; Dogs; Dose-Response Relationship, Drug; Double-Blind Method; Drug Discovery - methods; Humans; Imidazoles - pharmacokinetics; Male; Orexin Receptor Antagonists - pharmacokinetics; Pyrrolidines - pharmacokinetics; Rats; Rats, Wistar; σg; DMSO; PBPK-PD; SB-649868; AUC; ADAM; LC-MS/MS; G418; AUC0-last; OxA; DORA; ACT-605143; ACT-658090; EMG; MK-1064; Cmax; ROt1/2; EEG; OX2; CL; OX1; ACT-541468; CLint; logD; PD; CRC; Kb; Tmax; Vss; PK; REM

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 bra...