title: Mechanism-based pharmacokinetic/pharmacodynamic modeling of rat prefrontal cortical dopamine response to dual acting norepinephrine reuptake inhibitor and 5-HT1A partial agonist.
abstract: Evidence suggests that compounds possessing both norepinephrine reuptake inhibition and 5-HT(1A) partial agonism (NRI/5-HT(1A)) activities may have a greater efficacy in treating neuropsychiatric disorders than compounds possessing either activity alone. The objectives of the present study were first to characterize the pharmacokinetic/pharmacodynamic (PK/PD) relationship of the plasma concentrations of atomoxetine (NRI) and buspirone (5-HT(1A) partial agonist), administered alone and in combination, on the prefrontal cortex dopamine levels in rats, and second to use the model developed to characterize the PK/PD relationship of novel NRI/5-HT(1A) compounds, PF-04269339 and PF-03529936, in a NRI/5-HT(1A) drug discovery program. Maximal dopamine elevation was twofold higher after administration of atomoxetine and buspirone in combination, PF-04269339, or PF-03529936 than after administration of atomoxetine or buspirone alone. A mechanism-based extended indirect response model characterized the time profiles of the prefrontal cortex dopamine response to atomoxetine and buspirone, administered alone or in combination. After fixing three mechanism-specific pharmacodynamic parameters (I                         (max) and γ2 for NRI and γ1 for 5-HT(1A)) based on the model for atomoxetine and/or buspirone, the model fitted the exposure-response profiles of PF-04269339 and PF-03529936 well. Good in vitro-to-in vivo correlation was demonstrated with the compound-specific pharmacodynamic parameters (IC(50) for NRI and SC(50) and S                         (max) for 5-HT(1A)) across the compounds. In summary, a piecewise modeling approach was used successfully for the characterization of the PK/PD relationship of novel NRI/5-HT(1A) compounds on prefrontal cortex dopamine levels in rats. The application and value of the mechanism-based modeling in the dual pharmacology drug discovery program are also discussed.
authors.affiliation: Department of Pharmacokinetics Dynamics and Metabolism, Global Research and Development, Pfizer Inc., Cambridge, Massachusetts 02140, USA. Cheryl.Li@pfizer.com
authors.forename: Cheryl Shuang-wu
authors.initials: CS
authors.lastname: Li
authors.forename: Liming
authors.initials: L
authors.lastname: Zhang
authors.forename: Taraneh
authors.initials: T
authors.lastname: Haske
authors.forename: Amy
authors.initials: A
authors.lastname: Dounay
authors.forename: David
authors.initials: D
authors.lastname: Gray
authors.forename: Nancy
authors.initials: N
authors.lastname: Barta
authors.forename: Joanne
authors.initials: J
authors.lastname: Brodfuehrer
authors.forename: Christopher
authors.initials: C
authors.lastname: Lepsy
authors.forename: Brian
authors.initials: B
authors.lastname: Campbell
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000493:pharmacokinetics*; D000818:Animals; D000069445:Atomoxetine Hydrochloride; D002065:Buspirone / Q000493:pharmacokinetics; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D054333:Drug Partial Agonism; D006801:Humans; D008297:Male; D008954:Models, Biological; D009638:Norepinephrine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D011437:Propylamines / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D058825:Serotonin 5-HT1 Receptor Agonists / Q000493:pharmacokinetics*
chemical_list: D018759:Adrenergic Uptake Inhibitors; D011437:Propylamines; D058825:Serotonin 5-HT1 Receptor Agonists; D000069445:Atomoxetine Hydrochloride; D002065:Buspirone; D004298:Dopamine; D009638:Norepinephrine