PII-002 - APPLICATIONS AND LIMITATIONS OF 4ΒETA-HYDROXYCHOLESTEROL AS A SENSITIVE ENDOGENOUS BIOMARKER

A. Karkhanis¹, M. Harwood², F. Stader³, F. Bois², S. Neuhoff²; ¹Certara UK, Sheffield, South Yorkshire, England, ²Certara UK, Sheffield, UK, ³Certara UK, Sheffield, United Kingdom.

Background: Rifampicin, a pregnane X receptor (PXR) activator, induces cytochrome P450 (CYP)3A, leading to elevated plasma levels of 4β-hydroxycholesterol (4β-OHC), a CYP3A-specific metabolite of cholesterol. The metabolite itself, however, is metabolized by CYP7A1, and PXR activation also represses CYP7A1 expression as a protective feedback mechanism against the accumulation of bile acids in the liver. Thus, the impact of CYP7A1 suppression on the 4β-OHC plasma levels warrants evaluation.

Methods: We used physiologically based pharmacokinetic (PBPK) models of cholesterol, and its metabolite, 4β-OHC, developed for the Simcyp PBPK Simulator (V23R2, Certara Ltd. UK). Relevant physicochemical properties and metabolic pathway data for CYP3A and CYP27A1 was already incorporated in the models, and we added the CYP7A1 specific elimination pathway for the metabolite.

Results: The updated 4β-OHC PBPK model recovered (1) the observed baseline plasma levels in Japanese, Korean, and Caucasian populations; (2) the lower baseline 4β-OHC levels in males compared to females, indicative of sex-specific differences in CYP3A abundance; and (3) the altered 4β-OHC levels in disease populations such as Rheumatoid Arthritis patients. In addition, after multiple-dose treatment with PXR-activators such as rifampicin, the model described the reported increased 4β-OHC plasma levels. Up to 46% of the 4β-OHC plasma level changes, for some virtual individuals, were a direct result of CYP7A1 metabolite elimination pathway suppression. Individuals with high increase in 4β-OHC showed an up to 4-fold higher CYP7A1 abundance compared to individuals with low fold increase of 4β-OHC plasma levels.

Conclusion: CYP7A1 suppression data for PXR-inducers warrant determination. This would allow separating the increased synthesis of the metabolite due to CYP3A induction and the reduced metabolism of the metabolite due to CYP7A1 suppression. Nevertheless, this study provides a quantitative fit-for-purpose and framed-for-future modelling framework for an endogenous biomarker to evaluate the DDI risk due to hepatic CYP3A induction and assess the possible relevance of CYP7A1 suppression.