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

Abstract

1. This study optimized the reported approach for the prediction of drug–drug interactions (DDIs) using hepatocytes suspended in serum (HHSS) and provided a practical usage of HHSS in the early and late phases of drug discovery.

2. First, the IC₅₀ was determined using HHSS and evaluated as a qualitative index for DDI risks in the early phase. A retrospective study on clinical DDI cases revealed that inhibitors with IC₅₀ < 100 μmol/L caused clinical DDIs while those with IC₅₀ > 100 μmol/L showed weak or no potential for DDIs. Meanwhile, a pragmatic cutoff value could not be determined using previously reported K_i values of recombinant human cytochrome P450s.

3. Second, for a more substantial DDI risk assessment in the later phase, quantitative predictions of clinical DDI based on a static model were attempted by optimizing the most appropriate inhibitor concentration ([I]). The use of hepatic input plasma concentrations as a surrogate for [I] achieved the most successful predictions of the magnitude of increase in the AUC (within a 2-fold range of the observed values for 93.8% of inhibitors).

4. Through this study, we proposed the practical application of HHSS for an effective workflow to explore and profile candidates with less DDI liability.

• CYP inhibition
• cytochrome P450
• drug–drug interaction
• drug metabolism
• hepatocytes
• pharmacokinetics
• plasma protein binding
• serum