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The Use of HepaRG and Human Hepatocyte Data in Predicting CYP Induction Drug-Drug Interactions via Static Equation and Dynamic Mechanistic Modelling Approaches

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The method of predicting CYP induction drug-drug interactions (DDIs) from a relative induction score (RIS) calibration has been developed to provide a novel model facilitating predictions for any CYP-inducer substrate combination by inclusion of parameters such as the fraction of hepatic clearance mediated by a specific CYP and fraction of the dose escaping intestinal extraction. In vitro HepaRG CYP3A4 induction data were used as a basis for the approach and a large number of DDIs were well predicted. Primary human hepatocyte data were also used to make predictions, using the HepaRG calibration as a foundation. Similar predictive accuracy suggests that HepaRG and primary hepatocyte data can be used inter-changeably within the same laboratory. A comparison of this ‘indirect’ calibration method with a direct in vitro-in vivo scaling approach was made and investigations undertaken to define the most appropriate in vivo inducer concentration to use. Additionally, a reasonably effective prediction model based on F2 (the concentration of inducer taken to increase the CYP mRNA 2-fold above background) was established. An accurate prediction for the CYP1A2-dependent omeprazolecaffeine interaction was also made, demonstrating that the methods are useful for the evaluation of DDIs from induction involving mechanisms other than PXR activation. Finally, a dynamic mechanistic model accounting for the simultaneous influence of CYP induction and reversible and irreversible CYP inhibition in both the liver and intestine was written to provide a prediction of the overall DDI when several interactions occur concurrently. The rationale for using the various models described, alongside commercially available prediction tools, at various stages of the drug discovery process is described.

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Keywords: CYP Induction; CYP3A4 Indusers; Cytochrome P450; Dexamethasone; HepaRG cells; Pragnane X receptor; The F2 Method; carbamazepine; cyclosporine; drug-drug interaction; efavirenz; erythromycin; glucocorticoid receptor; human hepatocytes; induction; ketoconazole; midazolam; phenobarbitone-antipyrene; phenytoin; plasma concentration; pleconaril; rifampicin; ritonavir; saquinavir; triazolam

Document Type: Research Article

Publication date: December 1, 2010

More about this publication?
  • Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism and disposition. The journal serves as an international forum for the publication of timely reviews in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the latest and most important developments. The journal covers the following areas:

    In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites and adducts.
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