Towards a quantitative framework for the prediction of DDIs arising from cytochrome P450 induction.
Although CYP induction is not generally considered to be as clinically relevant as CYP inhibition, there are important examples where induction has caused both therapeutic failure, due to insufficient exposure to parent drug, and toxicity, mediated by increased formation of reactive metabolites. Furthermore, while there has been considerable progress in the extrapolation of in vitro data to predict the in vivo consequences of enzyme inhibition, less attention has been given to the quantitative impact of enzyme induction as a mechanism of drug-drug interaction (DDI) and as a component of compound selection and early drug development. We discuss current approaches in the context of a mechanistic framework for the prediction of the extent and time-course of enzyme induction in vivo based on in vitro experimentation. Factors influencing the extent of DDI due to CYP induction are summarised, and areas deficient in information that would allow more accurate prediction within target populations are highlighted.
Almond
L M
LM
Simcyp Limited, John Street, Sheffield, UK. l.almond@simcyp.com
Yang
J
J
Jamei
M
M
Tucker
G T
GT
Rostami-Hodjegan
A
A
D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D004347:Drug Interactions / Q000502:physiology*; D004790:Enzyme Induction / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D005544:Forecasting / Q000379:methods*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008954:Models, Biological
D003577:Cytochrome P-450 Enzyme System