Predicting in vivo drug interactions from in vitro drug discovery data.
In vitro screening for drugs that inhibit cytochrome P450 enzymes is well established as a means for predicting potential metabolism-mediated drug interactions in vivo. Given that these predictions are based on enzyme kinetic parameters observed from in vitro experiments, the miscalculation of the inhibitory potency of a compound can lead to an inaccurate prediction of an in vivo drug interaction, potentially precluding a safe drug from advancing in development or allowing a potent inhibitor to 'slip' into the patient population. Here, we describe the principles underlying the generation of in vitro drug metabolism data and highlight commonly encountered uncertainties and sources of bias and error that can affect extrapolation of drug-drug interaction information to the clinical setting.
Wienkers
Larry C
LC
Amgen, 1201 Amgen Court West, Seattle, Washington 98119, USA. wienkers@amgen.com
Heath
Timothy G
TG
D003577:Cytochrome P-450 Enzyme System / Q000494:pharmacology; D015195:Drug Design; D004347:Drug Interactions; D006801:Humans; D008658:Inactivation, Metabolic / Q000502:physiology; D011237:Predictive Value of Tests; D009626:Terminology as Topic
D003577:Cytochrome P-450 Enzyme System