title: Prediction of oral pharmacokinetics of cMet kinase inhibitors in humans: physiologically based pharmacokinetic model versus traditional one-compartment model.
abstract: The objective of this study was to assess the physiologically based pharmacokinetic (PBPK) model for predicting plasma concentration-time profiles of orally available cMet kinase inhibitors, (R)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine (PF02341066) and 2-[4-(3-quinolin-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)-pyrazol-1-yl]-ethanol (PF04217903), in humans. The prediction accuracy of pharmacokinetics (PK) by PBPK modeling was compared with that of a traditional one-compartment PK model based on allometric scaling. The predicted clearance values from allometric scaling with the correction for the interspecies differences in protein binding were used as a representative comparison, which showed more accurate PK prediction in humans than the other methods. Overall PBPK modeling provided better prediction of the area under the plasma concentration-time curves for both PF02341066 (1.2-fold error) and PF04217903 (1.3-fold error) compared with the one-compartment PK model (1.8- and 1.9-fold errors, respectively). Of more importance, the simulated plasma concentration-time profiles of PF02341066 and PF04217903 by PBPK modeling seemed to be consistent with the observed profiles showing multiexponential declines, resulting in more accurate prediction of the apparent half-lives (t(1/2)): the observed and predicted t(1/2) values were, respectively, 10 and 12 h for PF02341066 and 6.6 and 6.3 h for PF04217903. The predicted t(1/2) values by the one-compartment PK model were 17 h for PF02341066 and 1.9 h for PF04217903. Therefore, PBPK modeling has the potential to be more useful and reliable for the PK prediction of PF02341066 and PF04217903 in humans than the traditional one-compartment PK model. In summary, the present study has shown examples to indicate that the PBPK model can be used to predict PK profiles in humans.
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development, San Diego, CA, USA. shinji.yamazaki@pfizer.com
authors.forename: Shinji
authors.initials: S
authors.lastname: Yamazaki
authors.forename: Judith
authors.initials: J
authors.lastname: Skaptason
authors.forename: David
authors.initials: D
authors.lastname: Romero
authors.forename: Sylvia
authors.initials: S
authors.lastname: Vekich
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Jones
authors.forename: Weiwei
authors.initials: W
authors.lastname: Tan
authors.forename: Keith D
authors.initials: KD
authors.lastname: Wilner
authors.forename: Tatiana
authors.initials: T
authors.lastname: Koudriakova
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000818:Animals; D001682:Biological Availability; D002478:Cells, Cultured; D000077547:Crizotinib; D004285:Dogs; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006207:Half-Life; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000378:metabolism; D008875:Middle Aged; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D011719:Pyrazines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D011720:Pyrazoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D011725:Pyridines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D014230:Triazoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D055815:Young Adult
chemical_list: C558663:2-(4-(3-quinolin-6-ylmethyl-3H-(1,2,3)triazolo(4,5-b)pyrazin-5-yl)pyrazol-1-yl)ethanol; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D011720:Pyrazoles; D011725:Pyridines; D014230:Triazoles; D000077547:Crizotinib; D019859:Proto-Oncogene Proteins c-met