Prediction of drug-drug interactions from in vitro induction data: application of the relative induction score approach using cryopreserved human hepatocytes.
Cytochrome P450 induction-mediated drug-drug interaction (DDI) is one of the major concerns in clinical practice and for the pharmaceutical industry. Previously, a novel approach [the relative induction score (RIS)] was developed using the Fa2N-4 immortalized human hepatocyte line and proposed as a tool for predicting magnitude of clinical DDIs caused by induction of CYP3A. The approach is based on combining in vitro induction parameters (EC(50) and E(max)) with the efficacious free plasma concentrations to calculate a relative induction score, which is correlated to the magnitude of clinical DDI for midazolam or ethinyl estradiol. To expand the applicability of the RIS model, we have measured induction caused by ten drugs in two different lots of human cryopreserved hepatocytes and correlated the data to clinical DDIs using the RIS. The results demonstrated that, as with Fa2N-4 hepatocytes, sigmoidal relationships can be derived between RIS and magnitude of induction of midazolam and ethinyl estradiol clearance in cryopreserved human hepatocytes. This study demonstrates the general applicability of the relative induction score approach using the human cryopreserved hepatocyte model to predict clinical DDI.
Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research & Development, Groton, Connecticut 06340, USA. odette.a.fahmi@pfizer.com
Odette A
OA
Fahmi
Sherri
S
Boldt
Mary
M
Kish
R Scott
RS
Obach
Larry M
LM
Tremaine
D015925:Cryopreservation; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D004347:Drug Interactions; D022781:Hepatocytes / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques
D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human