RT Journal Article
SR Electronic
T1 Modeling, Prediction, and in Vitro in Vivo Correlation of CYP3A4 Induction
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 2355
OP 2370
DO 10.1124/dmd.108.020602
VO 36
IS 11
A1 Shou, Magang
A1 Hayashi, Mike
A1 Pan, Yvonne
A1 Xu, Yang
A1 Morrissey, Kari
A1 Xu, Lilly
A1 Skiles, Gary L.
YR 2008
UL http://dmd.aspetjournals.org/content/36/11/2355.abstract
AB CYP3A4 induction is not generally considered to be a concern for safety; however, serious therapeutic failures can occur with drugs whose exposure is lower as a result of more rapid metabolic clearance due to induction. Despite the potential therapeutic consequences of induction, little progress has been made in quantitative predictions of CYP3A4 induction-mediated drug-drug interactions (DDIs) from in vitro data. In the present study, predictive models have been developed to facilitate extrapolation of CYP3A4 induction measured in vitro to human clinical DDIs. The following parameters were incorporated into the DDI predictions: 1) EC50 and Emax of CYP3A4 induction in primary hepatocytes; 2) fractions unbound of the inducers in human plasma (fu, p) and hepatocytes (fu, hept); 3) relevant clinical in vivo concentrations of the inducers ([Ind]max, ss); and 4) fractions of the victim drugs cleared by CYP3A4 (fm, CYP3A4). The values for [Ind]max, ss and fm, CYP3A4 were obtained from clinical reports of CYP3A4 induction and inhibition, respectively. Exposure differences of the affected drugs in the presence and absence of the six individual inducers (bosentan, carbamazepine, dexamethasone, efavirenz, phenobarbital, and rifampicin) were predicted from the in vitro data and then correlated with those reported clinically (n = 103). The best correlation was observed (R2 = 0.624 and 0.578 from two hepatocyte donors) when fu, p and fu, hept were included in the predictions. Factors that could cause over- or underpredictions (potential outliers) of the DDIs were also analyzed. Collectively, these predictive models could add value to the assessment of risks associated with CYP3A4 induction-based DDIs by enabling their determination in the early stages of drug development. The American Society for Pharmacology and Experimental Therapeutics