Risk assessment of drug-drug interactions using hepatocytes suspended in serum during the drug discovery process.
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 Ki 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.
Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , Kanagawa , Japan.
Yohei
Y
Kosugi
Hideki
H
Hirabayashi
Tomoko
T
Igari
Yasushi
Y
Fujioka
Teruaki
T
Okuda
Toshiya
T
Moriwaki
D019540:Area Under Curve; D001769:Blood; D002478:Cells, Cultured; D015925:Cryopreservation; D016207:Cytokines / Q000378:metabolism; D055808:Drug Discovery; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000737:chemistry; D022781:Hepatocytes / Q000166:cytology* / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D011994:Recombinant Proteins / Q000737:chemistry; D018570:Risk Assessment
D016207:Cytokines; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins