title: PhRMA CPCDC initiative on predictive models of human pharmacokinetics, part 1: goals, properties of the PhRMA dataset, and comparison with literature datasets.
abstract: This study is part of the Pharmaceutical Research and Manufacturers of America (PhRMA) initiative on predictive models of efficacy, safety, and compound properties. The overall goal of this part was to assess the predictability of human pharmacokinetics (PK) from preclinical data and to provide comparisons of available prediction methods from the literature, as appropriate, using a representative blinded dataset of drug candidates. The key objectives were to (i) appropriately assemble and blind a diverse dataset of in vitro, preclinical in vivo, and clinical data for multiple drug candidates, (ii) evaluate the dataset with empirical and physiological methodologies from the literature used to predict human PK properties and plasma concentration-time profiles, (iii) compare the predicted properties with the observed clinical data to assess the prediction accuracy using routine statistical techniques and to evaluate prediction method(s) based on the degree of accuracy of each prediction method, and (iv) compile and summarize results for publication. Another objective was to provide a mechanistic understanding as to why one methodology provided better predictions than another, after analyzing the poor predictions. A total of 108 clinical lead compounds were collected from 12 PhRMA member companies. This dataset contains intravenous (n = 19) and oral pharmacokinetic data (n = 107) in humans as well as the corresponding preclinical in vitro, in vivo, and physicochemical data. All data were blinded to protect the anonymity of both the data and the company submitting the data. This manuscript, which is the first of a series of manuscripts, summarizes the PhRMA initiative and the 108 compound dataset. More details on the predictability of each method are reported in companion manuscripts.
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: Hannah M
authors.initials: HM
authors.lastname: Jones
authors.forename: Rhys Do
authors.initials: RD
authors.lastname: Jones
authors.forename: James W T
authors.initials: JW
authors.lastname: Yates
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Gibson
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: 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: M Sherry
authors.initials: MS
authors.lastname: Ku
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; D006801:Humans; D033183:Interdisciplinary Communication; D008954:Models, Biological; D015233:Models, Statistical; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D010599:Pharmacokinetics; D016730:Program Development; D015397:Program Evaluation; D015203:Reproducibility of Results; D018570:Risk Assessment; D012307:Risk Factors; D013045:Species Specificity
chemical_list: D004364:Pharmaceutical Preparations