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

  title={The Use of Physiology-Based Pharmacokinetic and Pharmacodynamic Modeling in the Discovery of the Dual Orexin Receptor Antagonist ACT-541468},
  author={Alexander Treiber and Ruben de Kanter and Catherine Roch and John Gatfield and Christoph Boss and Markus von Raumer and Benno Schindelholz and Clemens Muehlan and Joop M A van Gerven and François Jenck},
  journal={The Journal of Pharmacology and Experimental Therapeutics},
  pages={489 - 503}
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… 

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Accelerated Development of the Dual Orexin Receptor Antagonist ACT‐541468: Integration of a Microtracer in a First‐in‐Human Study

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Clinical pharmacology of the dual orexin receptor antagonist ACT-541468 in elderly subjects: Exploration of pharmacokinetics, pharmacodynamics and tolerability following single-dose morning and repeated-dose evening administration

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A Comprehensive Review of Daridorexant, a Dual-Orexin Receptor Antagonist as New Approach for the Treatment of Insomnia

The use of daridorexant is considered safe, with no clinically significant side-effects including deprivation of next-morning residual effects, including pharmacodynamics, animal and human research, pharmacokinetics and safety.



Phase I studies on the safety, tolerability, pharmacokinetics and pharmacodynamics of SB-649868, a novel dual orexin receptor antagonist

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DORAs, with a half-life exceeding 8 h in humans, are expected to fulfill this requirement as exposures drop to sub-threshold receptor occupancy levels prior to the wake period, potentially avoiding next-day residual effects at therapeutic doses.

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The use of physiology-based PK and PD modeling in the discovery of the dual orexin receptor antagonist ACT-541468

Departments of Preclinical Drug Metabolism and Pharmacokinetics, Center for Human Drug Research, Leiden, The Netherlands and Preclinical Development, Allschwil, Switzerland are represented.

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The evidence that an OX2R antagonist should be at least equivalent, or perhaps superior, to a DORA for the treatment of insomnia is reviewed, with a view to finding the ideal orexin agent to achieve a balanced increase in REM and non-rapid eye movement (NREM) sleep.

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Results indicate that additional blockade of OX1R to OX2R antagonism elicits a dysregulation of REM sleep by shifting the balance in favor ofREM sleep at the expense of NREM sleep that may increase the risk of adverse events.