title: Kinetic analysis of drug-target interactions with PET for characterization of pharmacological hysteresis.
abstract: In vivo characterization of the brain pharmacokinetics of novel compounds provides important information for drug development decisions involving dose selection and the determination of administration regimes. In this context, the compound-target affinity is the key parameter to be estimated. However, if compounds exhibit a dynamic lag between plasma and target bound concentrations leading to pharmacological hysteresis, care needs to be taken to ensure the appropriate modeling approach is used so that the system is characterized correctly and that the resultant estimates of affinity are correct. This work focuses on characterizing different pharmacokinetic models that relate the plasma concentration to positron emission tomography outcomes measurements (e.g., volume of distribution and target occupancy) and their performance in estimating the true in vivo affinity. Measured (histamine H3 receptor antagonist--GSK189254) and simulated data sets enabled the investigation of different modeling approaches. An indirect pharmacokinetic-receptor occupancy model was identified as a suitable model for the calculation of affinity when a compound exhibits pharmacological hysteresis.
authors: GlaxoSmithKline, Clinical Imaging Centre, Hammersmith Hospital, London, UK.
authors: Cristian
authors: C
authors: Salinas
authors: David
authors: D
authors: Weinzimmer
authors: Graham
authors: G
authors: Searle
authors: David
authors: D
authors: Labaree
authors: Jim
authors: J
authors: Ropchan
authors: Yiyun
authors: Y
authors: Huang
authors: Eugenii A
authors: EA
authors: Rabiner
authors: Richard E
authors: RE
authors: Carson
authors: Roger N
authors: RN
authors: Gunn
mesh_terms: D000465:Algorithms; D000818:Animals; D001552:Benzazepines / Q000097:blood* / Q000493:pharmacokinetics* / Q000494:pharmacology; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D003198:Computer Simulation; D005260:Female; D054828:Histamine H3 Antagonists / Q000097:blood* / Q000493:pharmacokinetics* / Q000494:pharmacology; D007700:Kinetics; D008954:Models, Biological; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D010215:Papio; D049268:Positron-Emission Tomography / Q000379:methods*
chemical_list: D001552:Benzazepines; D054828:Histamine H3 Antagonists; D009536:Niacinamide; C521312:6-((3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy)-N-methyl-3-pyridinecarboxamide
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