PWI-002 - 4Β-OH CHOLESTEROL AS ENDOGENOUS BIOMARKER FOR CYP3A4 INDUCER DDI STUDIES – A PBPK PLATFORM FOR IN SILICO COMPOUND TESTING.

P. Balazki¹, F. Martins¹, G. Montaseri², A. Schuler-Metz², R. Grempler³, S. Schaller¹, P. Stopfer², J. Gómez Mantilla²; ¹esqLABS GmbH, Saterland, Germany, ²Boehringer Ingelheim, Biberach, Germany, ³Boehringer Ingelheim, Ridgefield, CT, USA.

Background: The potency of new drug candidates to induce CYP-mediated metabolism and, by that, to be involved in drug-drug-interactions (DDI) is assessed in clinical studies by co-administration of sensitive index substrates such as midazolam. 4β-OH cholesterol (4bOH) is an endogenous biomarker for hepatic CYP3A4 induction which can be more conveniently incorporated in Phase I trials.

Methods: A PBPK model of cholesterol and its metabolite 4bOH was developed with the Open Systems Pharmacology (OSP) Suite and coupled with published inducer and victim models from the OSP CYP3A4-DDI network. The model was calibrated with published 4bOH data from perturbation scenarios with rifampicin, efavirenz, and carbamazepine as CYP3A4 inducers. 32 DDI scenarios from the qualified data base have been simulated and AUC ratios (AUCR) reported for index substrates were compared with predicted 4bOH AUCR.

Results: The model includes endogenous production of cholesterol in gut and liver, cholesterol conversion to 4bOH by CYP3A4 and its residual hepatic clearance. 4bOH is eliminated via hepatic clearance.

The model accurately describes observed increase in 4bOH concentrations after administration of CYP3A4 inducers. Predicted median 4bOH AUCR is 2.7, 1.87, 1.53 and 1.12 to discriminate among strong, moderate, mild and no induction classifications, respectively.

Conclusion: The developed PBPK model enables the use of 4bOH to investigate not only hepatic but also intestinal induction of CYP3A4. Based on simulation results, 4bOH has sensitivity comparable with midazolam oral and IV administration. The model allows extrapolation of measured 4bOH induction data to predict the effect of potential CYP3A4 inducer on index substrates in cost-effective way without exposing test subjects to the latter.