The Quantitative Prediction of In Vivo Enzyme-Induction Caused by Drug Exposure from In Vitro Information on Human Hepatocytes

Abstract

There have been no reports of the quantitative prediction of induction for drug-metabolizing enzymes in humans. We have tried to predict such enzyme induction in humans from in vitro data obtained using human hepatocytes. The in vitro and in vivo data on enzyme induction by inducers, such as rifampicin, phenobarbital and omeprazole, were collected from the published literature. The degree of enzyme induction in humans was compared with that predicted from in vitro data on human hepatocytes. Using the in vivo data, we calculated the hepatic intrinsic clearance of typical CYP substrates, such as midazolam and caffeine, before and after inducer treatment and estimated the induction ratios of hepatic intrinsic clearance following treatment. In the in vitro studies, the amount of mRNA or enzyme and enzyme activity in human hepatocytes, with or without an inducer, were compared and the induction ratios were estimated. The unbound mean concentration was taken as an index of drug exposure and the induction ratios in the in vivo and in vitro studies were compared. The unbound mean concentrations of inducers used in the in vitro studies were higher than those in the in vivo studies. The maximum induction ratios by inducers in the in vitro studies were higher than those in the in vivo studies. The induction ratio for rifampicin, omeprazole, troglitazone, dexamethasone and phenobarbital increased as the unbound mean concentration increased to reach a constant value. The induction of CYP3A and 1A was analyzed by the Emax model. The maximum induction ratio (Emax) and the concentration at half maximum induction (EC50) for rifampicin, omeprazole, troglitazone, dexamethasone and phenobarbital were 12.3, 0.847 micromol/L, 2.36, 0.225 micromol/L, 6.86, 0.002 micromol/L, 8.30, 9.32 micromol/L, and 7.62, 58.4 micromol/L, respectively. The Emax and EC50 of omeprazole for CYP1A were 12.02 and 0.075 micromol/L, respectively. The predicted induction ratio of all those inducers, except for omeprazole, based on the Emax and EC50 values obtained from the in vitro data were similar to the observed values. On the whole, a good correlation between the observed and predicted induction ratio of omeprazole was observed (r=0.768, p<0.05), although the predicted induction ratio was higher than the observed value. In conclusion, the present study suggests that it is possible to predict quantitatively the CYP3A enzyme induction from hepatocyte data.

Modeling, Prediction, and in Vitro in Vivo Correlation of CYP3A4 Induction

“…6). Several laboratories have attempted to predict in vivo DDIs using a relative induction score (Ripp et al, 2006) or an induction ratio (Kato et al, 2005) measured in hepatocytes. In neither case, however, was f m, CYP3A4 incorporated into the models.…”

Evaluation of Calibration Curve–Based Approaches to Predict Clinical Inducers and Noninducers of CYP3A4 with Plated Human Hepatocytes

“…Calibration curve-based models can be developed by comparing the observed clinical change in area under the curve (AUC) of a probe substrate drug (such as midazolam for CYP3A4) for a set of known inducers/noninducers of the enzyme of interest, with various in vitro induction potency parameters, such as relative induction score (RIS) (Ripp et al, 2006), AUC/F 2 (Kanebratt and Andersson 2008), or C max /EC 50 (Fahmi and Ripp 2010) obtained from specific lots (donors) of cryopreserved hepatocytes. These models, as well as others (Kato et al, 2005;Shou et al, 2008, Fahmi et al, 2009, can be used to evaluate induction potential and risk of a clinical DDI. Recent guidance from the US Food and Drug Administration (FDA, 2012) and European Medicines Agency (EMA, 2013) suggest options for evaluating induction potential, ranging from simple, conservative models ("R 3 " and a predefined fold-induction threshold) to more complex models as mentioned earlier (e.g., mechanistic static models, physiologically-based pharmacokinetic models, RIS).…”

Simulation of Clinical Drug-Drug Interactions from Hepatocyte CYP3A4 Induction Data and Its Potential Utility in Trial Designs

“…Because of major species differences in the degree of response to inducers (Jones et al, 2000;Moore and Kliewer, 2000), there is an increasing demand for the use of human in vitro systems, such as immortalized cell lines (Goodwin et al, 1999), immortalized human hepatocytes (Mills et al, 2004;Ripp et al, 2006), and freshly isolated or cryopreserved human hepatocyte cultures Hewitt et al, 2007) for investigating the potential of P450 induction by drug candidates in humans. Using these in vitro systems, various mechanistic approaches have been proposed for deriving quantitative projections of clinical P450 induction-based DDIs, applying either mathematical prediction approaches (Kato et al, 2005;Fahmi et al, 2008;Shou et al, 2008;Kozawa et al, 2009) or calibration curve approaches (Ripp et al, 2006;Kanebratt and Andersson, 2008). Although some success has been achieved by these approaches, these methods focus on prediction of mean changes in the exposure of a victim drug in the presence of an inducer at a steadystate concentration (Almond et al, 2009;Chu et al, 2009).…”