title: Mechanistic pharmacokinetic modeling for the prediction of transporter-mediated disposition in humans from sandwich culture human hepatocyte data.
abstract: With efforts to reduce cytochrome P450-mediated clearance (CL) during the early stages of drug discovery, transporter-mediated CL mechanisms are becoming more prevalent. However, the prediction of plasma concentration-time profiles for such compounds using physiologically based pharmacokinetic (PBPK) modeling is far less established in comparison with that for compounds with passively mediated pharmacokinetics (PK). In this study, we have assessed the predictability of human PK for seven organic anion-transporting polypeptide (OATP) substrates (pravastatin, cerivastatin, bosentan, fluvastatin, rosuvastatin, valsartan, and repaglinide) for which clinical intravenous data were available. In vitro data generated from the sandwich culture human hepatocyte system were simultaneously fit to estimate parameters describing both uptake and biliary efflux. Use of scaled active uptake, passive distribution, and biliary efflux parameters as inputs into a PBPK model resulted in the overprediction of exposure for all seven drugs investigated, with the exception of pravastatin. Therefore, fitting of in vivo data for each individual drug in the dataset was performed to establish empirical scaling factors to accurately capture their plasma concentration-time profiles. Overall, active uptake and biliary efflux were under- and overpredicted, leading to average empirical scaling factors of 58 and 0.061, respectively; passive diffusion required no scaling factor. This study illustrates the mechanistic and model-driven application of in vitro uptake and efflux data for human PK prediction for OATP substrates. A particular advantage is the ability to capture the multiphasic plasma concentration-time profiles for such compounds using only preclinical data. A prediction strategy for novel OATP substrates is discussed.
authors.affiliation: Pfizer Worldwide R&D, Department of Pharmacokinetics, Dynamics and Metabolism, Sandwich, Kent, United Kingdom. hannah.jones@pfizer.com
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Jones
authors.forename: Hugh A
authors.initials: HA
authors.lastname: Barton
authors.forename: Yurong
authors.initials: Y
authors.lastname: Lai
authors.forename: Yi-An
authors.initials: YA
authors.lastname: Bi
authors.forename: Emi
authors.initials: E
authors.lastname: Kimoto
authors.forename: Sarah
authors.initials: S
authors.lastname: Kempshall
authors.forename: Sonya C
authors.initials: SC
authors.lastname: Tate
authors.forename: Ayman
authors.initials: A
authors.lastname: El-Kattan
authors.forename: J Brian
authors.initials: JB
authors.lastname: Houston
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Galetin
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Fenner
mesh_terms: D018929:Cell Culture Techniques; D002478:Cells, Cultured; D002627:Chemistry, Physical; D002851:Chromatography, High Pressure Liquid; D003198:Computer Simulation; D015925:Cryopreservation; D055808:Drug Discovery / Q000379:methods*; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007275:Injections, Intravenous; D008954:Models, Biological; D009928:Organ Specificity; D027361:Organic Anion Transporters / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*; D010599:Pharmacokinetics; D011237:Predictive Value of Tests; D013379:Substrate Specificity; D014018:Tissue Distribution
chemical_list: D027361:Organic Anion Transporters; D004364:Pharmaceutical Preparations