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Pharmacogenomics. 2016 Apr;17(6):615-31. doi: 10.2217/pgs.16.9. Epub 2016 Apr 5.

Assessment of drug metabolism enzyme and transporter pharmacogenetics in drug discovery and early development: perspectives of the I-PWG.

Author information

1
Sanofi, Translational Medicine and Early Development, 55 Corporate Drive, Bridgewater, NJ 08807, USA.
2
Pfizer Inc., Worldwide Research and Development, Department of Pharmacokinetics, Dynamics and Metabolism, Eastern Point Road, Groton, CT 06340, USA.
3
Biogen, Early Development Sciences, 14 Cambridge Center, Cambridge, MA 02142, USA.
4
Preclinical Pharmacokinetics and Metabolism, Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
5
Merck & Co, Pharmacodynamics, Pharmacokinetics and Drug Metabolism, 2000 Galloping Hill Road, Kenilworth, NJ07033, USA.
6
Eli Lilly and Company, Drug Disposition, LillyCorporate Center, Indianapolis, IN 46285, USA.
7
Novartis Pharmaceuticals, 1 Health Plaza, EastHanover, NJ 07936, USA.
8
Novartis Institutes for Biomedical Research, Drug Metabolism and Pharmacokinetics, One Health Plaza, East Hanover, NJ07936-1080, USA.
9
Pfizer Inc., Worldwide Research and Development, Department of Pharmacokinetics, Dynamics and Metabolism,10646 Science Center Drive, San Diego, CA 92121, USA.
10
Biogen, Preclinical PK and In vitro ADME, 14 Cambridge Center, Cambridge, MA 02142, USA.

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.

KEYWORDS:

drug metabolism enzyme; drug transporter; modeling; pharmacogenetics; pharmacokinetic variability; polymorphism; reaction phenotyping

PMID:
27045656
DOI:
10.2217/pgs.16.9
[Indexed for MEDLINE]

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