#DMD 40824 1 Predictive utility of in vitro rifampin induction data generated in fresh and cryopreserved human hepatocytes, Fa2N-4 and HepaRG cells

hepatic extraction ratio; AUC iv /AUC iv ind ratio of the i.v. victim drug AUC in the absence and presence of rifampin; DDI, drug-drug interaction, CHH, cryopreserved human hepatocytes; PHH, primary human hepatocytes This article has not been copyedited and formatted. The final version may differ from this version. Abstract Rifampin is a potent inducer of CYP3A4 in vitro and precipitates numerous drug-drug interactions (DDIs) when co-administered with CYP3A4 substrates. In the current study, we have critically assessed reported rifampin in vitro CYP3A4 induction data in Fa2N-4, HepaRG and cryopreserved or primary human hepatocytes, using either CYP3A4 mRNA or probe substrate metabolism as induction endpoints. An in vivo database of i.v. administered victim drugs (assuming hepatic induction only) was collated (n=18) to assess the predictive utility of these in vitro systems and to optimize rifampin in vivo E max. In addition, the effect of substrate hepatic extraction ratio on prediction accuracy was investigated using prediction boundaries proposed recently (Guest et al., 2011, Drug Metab Dispos 39:170-173). Incorporation of hepatic extraction ratio in the prediction model resulted in accurate prediction of 89% of i.v. induction DDIs (n=18), regardless of in vitro system or induction endpoint (mRNA or CYP3A4 activity). Effects of in vitro parameters from different cellular systems, and optimized in vivo E max , on the prediction of 21 oral DDIs were assessed. Use of mRNA data resulted in pronounced over-prediction across all systems, with 86-100% of DDIs outside the acceptable prediction limits; in contrast, CYP3A4 activity predicted up to 62% of the oral DDIs within limits. Although prediction accuracy of oral DDIs was improved when using i.v. optimized rifampin E max , >35% of DDIs were incorrectly assigned, suggesting potential differential E max between intestine and liver. Implications of the findings and recommendations for prediction of rifampin DDIs are discussed. This article has not been copyedited and formatted. The final version may differ from this version.