Comparison of predicted drug-drug interaction (DDI) liabilities from in vitro data to in vivo clinical studies

Hepatobiliary clearances, after in vitro to in vivo extrapolation (IVIVE), can be used to identify the rate-determining step (RDS) of a drug, such as if the CLmet + bile/CLsef ratio is > or < than the tipping point (eq. 2), then the drug will have RDSuptake or RDSall, respectively. If a drug has RDSuptake, then the PImet + bile can be quantified (eq. 5) to predict when a significant DDI should be expected owing to inhibition of metabolic/biliary efflux clearance. An expanded analysis is shown in Supplementary Table 1.

DrugHepatobiliary Clearance (ml/min per kg)fubCLsin/QhaCLmet + bile/CLsefTipping PointPImet + bileRDS In VitroRDS In VivoReference
Atorvastatin61b24.958. et al. (2014)
1194d24.958.>51%UptakeCamenisch and Umehara (2012)
405e24.958.34.30.772.522.26>10%UptakeKunze et al. (2015)
198b35964.611.80.800.212.22AllMaeda et al. (2011)
Bosentan132b28.919.55.80.360.872.95AllUptakecVarma et al. (2014)
142d28.919.55.80.380.872.90AllJones et al. (2012)
1117e28.919. et al. (2017)
Repaglinide166b63.61280. allhVarma et al. (2014)
1983d63.61280.32.322.011.21>40%UptakeJones et al. (2012)
1151e63.61280.31.352.011.71>15%UptakeYoshikado et al. (2017)
  • a The fub and Qh values as noted in each reference were used for analysis; note that fub may vary for the same drug across different references.

  • b In vitro quantified + IVIVE.

  • c RDSuptake was established in vivo for atorvastatin and bosentan since there was no significant AUC change to victim drugs when coadministered with intravenous itraconazole (CYP3A inhibitor) which resulted in 33% and 73% CYP3A inhibition, respectively (Maeda et al., 2011; Yoshikado et al., 2017). Midazolam, a CYP3A probe, was used to assess magnitude of CYP3A inhibition. RDSuptake was established for repaglinide via whole-body physiologically based pharmacokinetic (PBPK) modeling of complex transporter- and enzyme-mediated DDIs (Varma et al., 2013).

  • d In vitro quantified + IVIVE + empirical scaling factor for active uptake transport (individual scaling factor).

  • e In vitro quantified + IVIVE + empirical scaling factor for active uptake transport (geometric mean scaling factor).

  • f Composite CLmet + bile.

  • g Fitted parameters from in vivo using PBPK model.

  • h RDSall was established in vivo for repaglinide even though there was no change to systemic AUC by intravenous itraconazole because CYP2C8 is the major hepatic drug-metabolizing enzyme (Yoshikado et al., 2017). In a different study, oral trimethoprim, a selective CYP2C8 inhibitor, increased repaglinide AUC by 1.8-fold (Kim et al., 2016).