title: PHRMA CPCDC initiative on predictive models of human pharmacokinetics, part 5: prediction of plasma concentration-time profiles in human by using the physiologically-based pharmacokinetic modeling approach.
abstract: The objective of this study is to assess the effectiveness of physiologically based pharmacokinetic (PBPK) models for simulating human plasma concentration-time profiles for the unique drug dataset of blinded data that has been assembled as part of a Pharmaceutical Research and Manufacturers of America initiative. Combinations of absorption, distribution, and clearance models were tested with a PBPK approach that has been developed from published equations. An assessment of the quality of the model predictions was made on the basis of the shape of the plasma time courses and related parameters. Up to 69% of the simulations of plasma time courses made in human demonstrated a medium to high degree of accuracy for intravenous pharmacokinetics, whereas this number decreased to 23% after oral administration based on the selected criteria. The simulations resulted in a general underestimation of drug exposure (Cmax and AUC0- t ). The explanations for this underestimation are diverse. Therefore, in general it may be due to underprediction of absorption parameters and/or overprediction of distribution or oral first-pass. The implications of compound properties are demonstrated. The PBPK approach based on in vitro-input data was as accurate as the approach based on in vivo data. Overall, the scientific benefit of this modeling study was to obtain more extensive characterization of predictions of human PK from PBPK methods.
authors.affiliation: Leader Consultant, 4009 Sylvia Daoust, Québec city, Québec, Canada, G1X 0A6. patrick-poulin@videotron.ca.
authors.forename: Patrick
authors.initials: P
authors.lastname: Poulin
authors.forename: Rhys D O
authors.initials: RD
authors.lastname: Jones
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Jones
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Gibson
authors.forename: Malcolm
authors.initials: M
authors.lastname: Rowland
authors.forename: Jenny Y
authors.initials: JY
authors.lastname: Chien
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Ring
authors.forename: Kimberly K
authors.initials: KK
authors.lastname: Adkison
authors.forename: M Sherry
authors.initials: MS
authors.lastname: Ku
authors.forename: Handan
authors.initials: H
authors.lastname: He
authors.forename: Ragini
authors.initials: R
authors.lastname: Vuppugalla
authors.forename: Punit
authors.initials: P
authors.lastname: Marathe
authors.forename: Volker
authors.initials: V
authors.lastname: Fischer
authors.forename: Sandeep
authors.initials: S
authors.lastname: Dutta
authors.forename: Vikash K
authors.initials: VK
authors.lastname: Sinha
authors.forename: Thorir
authors.initials: T
authors.lastname: Björnsson
authors.forename: Thierry
authors.initials: T
authors.lastname: Lavé
authors.forename: James W T
authors.initials: JW
authors.lastname: Yates
mesh_terms: D022126:Access to Information; D061605:Administration, Intravenous; D000284:Administration, Oral; D000818:Animals; D003198:Computer Simulation; D003299:Cooperative Behavior; D062313:Databases, Pharmaceutical; D055808:Drug Discovery / Q000379:methods*; D004353:Drug Evaluation, Preclinical; D065569:Gastrointestinal Absorption; D006801:Humans; D033183:Interdisciplinary Communication; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D015233:Models, Statistical; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D010599:Pharmacokinetics; D016730:Program Development; D015397:Program Evaluation; D015203:Reproducibility of Results; D013045:Species Specificity
chemical_list: D004364:Pharmaceutical Preparations