Evaluating reversible inhibitory drug-drug interactions: enzyme kinetics, and in vitro-to-in vivo scaling models.

Abstract

Background: Polypharmacy is common in clinical practice, making the consideration of potential drug-drug interactions (DDIs) an important factor in clinical therapeutics. In vitro methods are applied for screening and anticipating possible DDIs, with mathematical models playing a key role in evaluating inhibitor potency and scaling pharmacokinetic parameters from in vitro data. Despite extensive research on this topic, varying assumptions and experimental settings across studies have led to inconsistency among models, with the possible consequence of misapplication of enzyme kinetic models and scaling procedures, and misdirection in DDI evaluation and predictions.

Methods: This study reviews and summarizes common enzyme kinetic models used to analyse substrate-enzyme-inhibitor interactions across six different mechanisms of inhibition, and derives the corresponding in vitro to in vivo scaling model for use in connecting to clinical DDI studies.

Results: A single operational equation was developed, along with a method for determining the inhibition mechanism and the connection to anticipation of in vivo pharmacokinetics.

Conclusion: Analysis based on the equation shows that, for inhibitors with the same inhibition constant (Ki), competitive inhibitors will pose a higher potential for DDIs compared to non-competitive inhibitors, while complete inhibitors will result in a higher potential for DDI than partial inhibitors.