Received for publication September 10, 2007.
Revised March 11, 2008.
Accepted for publication March 31, 2008.

PREDICTION OF PHARMACOKINETIC DRUG-DRUG INTERACTIONS USING HUMAN HEPATOCYTE SUSPENSION IN PLASMA AND CYP PHENOTYPIC DATA - PART II. IN VITRO-IN VIVO CORRELATION WITH KETOCONAZOLE

Abstract

Traditional drug-drug interaction (DDI) predictions are based on the ratio of an inhibitor's physiological concentration [I] and its inhibition constant Ki. Determining [I] at the enzymatic site though critical for predicting the clinical DDIs remains to be a technical challenge. In our previous study, a novel approach using cryopreserved human hepatocytes suspended in human plasma was investigated to mimic the in vivo concentration of ketoconazole at the enzymatic site (Lu et al., 2007), effectively eliminating the estimation of the elusive [I] value. The CYP inhibition in this system appears to model that in vivo. Using the ketoconazole inhibition information in human hepatocyte-plasma suspension together with quantitative CYP phenotypic information, we successfully predicted the pharmacokinetic DDIs for a small set of drugs, such as theophylline, tolbutamide, omeprazole, desipramine, midazolam, loratadine, cyclosporine, and alprazolam, as well as an investigational compound. For the applicability of this model on wider scale the in vitro-in vivo correlation data set needed to be expanded. However, for most drugs in the literature there is not enough quantitative information on the involvement of individual CYPs to predict DDIs retrospectively. To facilitate that, in this study we determined quantitative CYP phenotyping on 7 marketed drugs: budesonide, buprenorphine, loratadine, sinoclimus, tacrolimus, docetaxel, and methylprednisolone. Augmentation of the new data set with the one generated previously produced broader database that provided further support for the wider applicability of this approach using ketoconazole as a potent CYP3A inhibitor. This application is predicted to be equally effective with other CYP inhibitors that are not substrate of efflux pumps.

Key words: CYP inhibition, drug interactions, drug-drug interactions, hepatocytes, human CYP enzymes, in vitro-in vivo prediction, inhibition, isolated hepatocytes