In vitro-to-in vivo predictions of drug–drug interactions involving multiple reversible inhibitors

Abstract

Introduction: Predictions of drug–drug interactions (DDIs) are commonly performed for single inhibitors, but interactions involving multiple inhibitors also frequently occur. Predictions of such interactions involving stereoisomer pairs, parent/metabolite combinations and simultaneously administered multiple inhibitors are increasing in importance. This review provides the framework for predicting inhibitory DDIs of multiple inhibitors with any combination of reversible inhibition mechanism.

Areas covered: The review provides an overview of the reliability of the in vitro determined reversible inhibition mechanism. Furthermore, the article provides a method to predict DDIs for multiple reversible inhibitors that allows substituting the inhibition constant (K _i) with an inhibitor affinity (IC₅₀) value determined at S << K_M.

Expert opinion: A better understanding and the prediction methods of DDIs, resulting from multiple inhibitors, are important. The inhibition mechanism of a reversible inhibitor is often equivocal across studies and unreliable. Determination of the K _i requires the assignment of reversible inhibition mechanism but in vitro-to-in vivo prediction of DDI risk can be achieved for multiple inhibitors from estimates of the inhibitor affinity (IC₅₀) only, regardless of the inhibition mechanism.

Keywords::

• cytochrome P450
• drug–drug interactions
• in vitro-to-in vivo prediction
• inhibitory metabolites
• multiple inhibitors
• reversible inhibition

Acknowledgments

The authors wish to thank WM Atkins for helpful discussions in preparation of this manuscript.

Notes

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