IC₅₀-based approaches as an alternative method for assessment of time-dependent inhibition of CYP3A4

Abstract

1. The predictive utility of two in vitro methods (empirical IC₅₀-based and mechanistic k_inact/K_I) for the assessment of time-dependent cytochrome P450 3A4 (CYP3A4) inhibition has been compared.

2. IC₅₀ values were determined at multiple pre-incubation time points over 30 min for five CYP3A4 time-dependent inhibitors (verapamil, diltiazem, erythromycin, clarithromycin, and azithromycin). The ability of IC₅₀ data obtained following pre-incubation to predict k_inact/K_I parameters was investigated and its utility was assessed relative to the conventional k_inact/K_I model using 50 reported clinical drug–drug interactions (DDIs). Models with either hepatic or hepatic with intestinal components were explored.

3. For low/medium potency time-dependent inhibitors, 81% of the predicted k_inact/K_I(unbound) from IC₅₀ data were within an order of magnitude of the actual values, in contrast to 50% of potent inhibitors. An underprediction trend and > 50% of false-negatives were observed when IC₅₀ data were used in the DDI hepatic prediction model; incorporation of the intestine improved the prediction accuracy. On the contrary, 86% of the DDI studies were predicted within twofold using k_inact/K_I mechanistic approach and the combined hepatic and intestinal model.

4. Use of the empirical IC₅₀ approach as an alternative to the mechanistic k_inact/K_I model for in vivo DDI prediction is limited and is best restricted to preliminary investigations.

Keywords::

• Drug–drug interactions
• time-dependent inhibition
• CYP3A4

Acknowledgements

Declaration of interest

This work was funded by a consortium of pharmaceutical companies (GlaxoSmithKline, Lilly, Novartis, Pfizer and Servier) within the Centre for Applied Pharmacokinetic Research at the University of Manchester.