A simplified approach to predict CYP3A-mediated drug–drug interactions at early drug discovery: validation with clinical data

Abstract

1. The present study evaluates which factors should be incorporated into a simplified approach to reasonably predict CYP3A-mediated drug-drug interaction (DDI) at an early drug discovery stage. 2. CYP3A IC50 values were obtained using human liver microsomes (HLM) and hepatocytes. Plasma and microsomal protein binding and in vitro hepatocyte partition coefficient (Kp) were also determined for 10 drugs. Therapeutic human maximum plasma concentrations (Cmax) were retrieved from the literature. DDI predictions were performed using an equation incorporating the fraction of the substrate metabolized by CYP3A with the total or free plasma Cmax, with or without correction for hepatocyte Kp. 3. Based on the Ki data from HLM, the use of total Cmax provided a prediction of DDI within 2-fold of the observed clinical values for 9 out of 10 drugs. 4. In comparison, free drug corrections for both Cmax and Ki values from HLM led to an underprediction of DDI (>3-fold error for five drugs). 5. Data from hepatocytes showed, in general, lower prediction accuracy than data from HLM. 6. CYP3A-mediated DDIs can be predicted with a high level of accuracy based on Ki estimates from HLM data and the total therapeutic plasma Cmax of the inhibitors. This approach should be widely applicable to the assessment of clinically significant DDIs risk in early drug discovery programs.

Risk assessment of drug–drug interactions using hepatocytes suspended in serum during the drug discovery process

“…Therefore, evaluation of DDI potential is a crucial part of the drug discovery and development processes. Several in vitro methods have been developed to assess the potential risk of CYP inhibition (Bjornsson et al, 2003;Foti et al, 2010;McGinnity, 2005;Obach et al, 2005;Rioux et al, 2013;Turpeinen et al, 2006). The CYP inhibition screening is utilized for the structure optimization in the early drugdiscovery process.…”

Assessment of CYP3A‐mediated drug–drug interaction potential for victim drugs using an in vivo rat model

“…Well described procedures and guidance for DDI investigation have been published to predict clinically relevant interactions for CYP3A inhibitors . In fact, CYP3A mediated DDIs can be predicted with a high level of accuracy based only on in vitro K i estimates and the therapeutic C max of the inhibitors in early drug discovery programs, if the fraction of the victim drug metabolized by CYP3A is known .…”