Perspective: 4β-hydroxycholesterol as an emerging endogenous biomarker of hepatic CYP3A

Abstract

A key goal in the clinical development of a new molecular entity is to quickly identify whether it has the potential for drug–drug interactions. In particular, confirmation of in vitro data in the early stage of clinical development would facilitate the decision making and inform future clinical pharmacology study designs. Plasma 4β-hydroxycholesterol (4β-HC) is considered as an emerging endogenous biomarker for cytochrome P450 3A (CYP3A), one of the major drug metabolizing enzymes. Although there are increasing reports of the use of 4β-HC in academic- and industry-sponsored clinical studies, a thorough review, summary and consideration of the advantages and challenges of using 4β-HC to evaluate changes in CYP3A activity has not been attempted. Herein, we review the biology of 4β-HC, its response to treatment with CYP3A inducers, inhibitors and mixed inducer/inhibitors in healthy volunteers and patients, the association of 4β-HC with other probes of CYP3A activity (e.g. midazolam, urinary cortisol ratios), and present predictive pharmacokinetic models. We provide recommendations for studying hepatic CYP3A activity in clinical pharmacology studies utilizing 4β-HC at different stages of drug development.

Keywords:

• 4?-Hydroxycholesterol
• CYP3A
• endogenous
• biomarker
• induction
• inhibition
• clinical
• drug development

Acknowledgements

This material was developed with the support of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ), a not-for-profit organization of pharmaceutical and biotechnology companies with a mission of advancing science-based and scientifically-driven standards and regulations for pharmaceutical and biotechnology products worldwide (please visit www.iqconsortium.org for more information). Given the increasing interest in understanding how to utilize the 4β-HC as a hepatic CYP3A biomarker in clinical pharmacology studies, a group comprising industrial and academic scientists with expertise in drug metabolism and clinical pharmacology was assembled under the umbrella of IQ Consortium Drug Metabolism and Clinical Pharmacology Leadership Groups.

We would like to thank the members of the IQ 4β-hydroxycholesterol biomarker working group for their support during the research and writing of this paper, and we are grateful for the critical review from IQ Drug Metabolism and Clinical Pharmacology Leadership Groups.

Disclosure statement

The authors declared no conflict of interest.