Prediction of CYP-mediated drug interactions in vivo using in vitro data.
Over the past 15 years, a concerted effort has been undertaken by the pharmaceutical industry to reduce the attrition of clinical candidates resulting from undesirable ADME characteristics. Increasing regulatory and competitive pressures demand that pharmaceutical products brought to the market possess pristine safety and drug co-administration profiles for most therapeutic areas. The high-profile withdrawal of drugs such as mibefradil from the market because of unfavorable drug-drug interaction profiles has focused efforts on screening for cytochrome P450 (CYP)-mediated drug interactions early in the discovery paradigm and on predicting the impact of inhibition on the in vivo situation. This paper discusses current practices used to screen for CYP-mediated drug-drug interactions in vitro (inhibition and induction) and how these data are being used to predict whether a clinically relevant drug-drug interaction is likely to occur in vivo.
Foti
Robert S
RS
Amgen Inc, 1201 Amgen Court W, Seattle, WA 98119, USA.
Wahlstrom
Jan L
JL
D000818:Animals; D003198:Computer Simulation; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000502:physiology*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System