title: Assessment of drug metabolism enzyme and transporter pharmacogenetics in drug discovery and early development: perspectives of the I-PWG.
abstract: Genetic variants of drug metabolism enzymes and transporters can result in high pharmacokinetic and pharmacodynamic variability, unwanted characteristics of efficacious and safe drugs. Ideally, the contributions of these enzymes and transporters to drug disposition can be predicted from in vitro experiments and in silico modeling in discovery or early development, and then be utilized during clinical development. Recently, regulatory agencies have provided guidance on the preclinical investigation of pharmacogenetics, for application to clinical drug development. This white paper summarizes the results of an industry survey conducted by the Industry Pharmacogenomics Working Group on current practice and challenges with using in vitro systems and in silico models to understand pharmacogenetic causes of variability in drug disposition.
authors.affiliation: Sanofi, Translational Medicine and Early Development, 55 Corporate Drive, Bridgewater, NJ 08807, USA.
authors.forename: William
authors.initials: W
authors.lastname: Brian
authors.affiliation: Pfizer Inc., Worldwide Research and Development, Department of Pharmacokinetics, Dynamics and Metabolism, Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Larry M
authors.initials: LM
authors.lastname: Tremaine
authors.affiliation: Biogen, Early Development Sciences, 14 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Million
authors.initials: M
authors.lastname: Arefayene
authors.affiliation: Preclinical Pharmacokinetics and Metabolism, Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Ruben
authors.initials: R
authors.lastname: de Kanter
authors.affiliation: Merck & Co, Pharmacodynamics, Pharmacokinetics and Drug Metabolism, 2000 Galloping Hill Road, Kenilworth, NJ07033, USA.
authors.forename: Raymond
authors.initials: R
authors.lastname: Evers
authors.affiliation: Eli Lilly and Company, Drug Disposition, LillyCorporate Center, Indianapolis, IN 46285, USA.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Novartis Pharmaceuticals, 1 Health Plaza, EastHanover, NJ 07936, USA.
authors.forename: James
authors.initials: J
authors.lastname: Kalabus
authors.affiliation: Novartis Institutes for Biomedical Research, Drug Metabolism and Pharmacokinetics, One Health Plaza, East Hanover, NJ07936-1080, USA.
authors.forename: Wen
authors.initials: W
authors.lastname: Lin
authors.affiliation: Pfizer Inc., Worldwide Research and Development, Department of Pharmacokinetics, Dynamics and Metabolism,10646 Science Center Drive, San Diego, CA 92121, USA.
authors.forename: Cho-Ming
authors.initials: CM
authors.lastname: Loi
authors.affiliation: Biogen, Preclinical PK and In vitro ADME, 14 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Guangqing
authors.initials: G
authors.lastname: Xiao
mesh_terms: D055808:Drug Discovery / Q000379:methods; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics*; D026901:Membrane Transport Proteins / Q000235:genetics*; D010597:Pharmacogenetics / Q000379:methods
chemical_list: D026901:Membrane Transport Proteins
keywords: drug metabolism enzyme; drug transporter; modeling; pharmacogenetics; pharmacokinetic variability; polymorphism; reaction phenotyping