J Clin Pharmacol
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DRUG DEVELOPMENT

The Conduct of In Vitro and In Vivo Drug-Drug Interaction Studies: A PhRMA Perspective

Thorir D. Bjornsson, John T. Callaghan, Heidi J. Einolf, Volker Fischer, Lawrence Gan, Scott Grimm, John Kao, S. Peter King, Gerald Miwa, Lan Ni, Gondi Kumar, James McLeod, Scott R. Obach, Stanley Roberts, Amy Roe, Anita Shah, Fred Snikeris, John T. Sullivan, Donald Tweedie, Jose M. Vega, John Walsh and Steven A. Wrighton

From Abbott Laboratories, Abbott Park, Illinois (Dr. Roberts); Amgen, Thousand Oaks, California (Dr. Kumar, Dr. Sullivan); AstraZeneca Pharmaceuticals LP, Wilmington, Delaware (Dr. Grimm); Aventis, Bridgewater, New Jersey (Dr. King); Bayer Corporation, West Haven, Connecticut (Dr. Shah); Boehringer Ingelheim Corporation, Ridgefield, Connecticut (Dr. Tweedie); Eli Lilly and Company, Indianapolis, Indiana (Dr. Callaghan, Dr. Ni, Dr. Wrighton); GlaxoSmithKline, Research Triangle Park, North Carolina (Dr. Walsh); Merck Research Laboratories, West Point, Pennsylvania (Dr. Vega); Millennium Pharmaceuticals, Cambridge, Massachusetts (Dr. Gan, Dr. Miwa); Novartis Pharmaceuticals Corporation, East Hanover, New Jersey (Dr. Einolf, Dr. Fischer, Dr. McLeod); Pfizer, Groton, Connecticut (Dr. Obach); Procter & Gamble, Cincinnati, Ohio (Dr. Roe); Sanofi-Syntelabo, Malvern, Pennsylvania (Dr. Snikeris); and Wyeth, Collegeville, Pennsylvania (Dr. Bjornsson, Dr. Kao).

Current regulatory guidances do not address specific study designs for in vitro and in vivo drug-drug interaction studies. There is a common desire by regulatory authorities and by industry sponsors to harmonize approaches to allow for a better assessment of the significance of findings across different studies and drugs. There is also a growing consensus for the standardization of cytochrome P450 (CYP) probe substrates, inhibitors, and inducers and for the development of classification systems to improve the communication of risk to health care providers and patients. While existing guidances cover mainly CYP-mediated drug interactions, the importance of other mechanisms, such as transporters, has been recognized more recently and should also be addressed. This paper was prepared by the Pharmaceutical Research and Manufacturers of America (PhRMA) Drug Metabolism and Clinical Pharmacology Technical Working Groups and represents the current industry position. The intent is to define a minimal best practice for in vitro and in vivo pharmacokinetic drug-drug interaction studies targeted to development (not discovery support) and to define a data package that can be expected by regulatory agencies in compound registration dossiers.

Key Words: Drug-drug interactions • cytochrome P450 • PhaseII enzymes • drug transporters • CYP inhibitor

Address for reprints: Jose M. Vega, Merck Research Laboratories, WP 75A-303, Merck & Co., West Point, PA 19486.






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