title: 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.
authors.affiliation: a Drug Metabolism and Pharmacokinetics , Genentech , South San Francisco , CA , USA.
authors.forename: Jialin
authors.initials: J
authors.lastname: Mao
authors.affiliation: b Pharmacokinetics, Pharmacodynamics and Drug Metabolism , Merck , Boston , MA , USA.
authors.forename: Iain
authors.initials: I
authors.lastname: Martin
authors.affiliation: c Drug Development , Galleon Pharmaceuticals , Horsham , PA , USA.
authors.forename: James
authors.initials: J
authors.lastname: McLeod
authors.affiliation: d Drug Metabolism and Pharmacokinetics , GlaxoSmithKline , Hertfordshire , UK.
authors.forename: Gail
authors.initials: G
authors.lastname: Nolan
authors.affiliation: e Translational Medicine and Early Development , Sanofi , Bridgewater , NJ , USA.
authors.forename: Robert
authors.initials: R
authors.lastname: van Horn
authors.affiliation: f Clinical Pharmacology , Pfizer , New York , NY , USA.
authors.forename: Manoli
authors.initials: M
authors.lastname: Vourvahis
authors.affiliation: g Department of Pharmaceutics , University of Washington , Seattle , WA , USA.
authors.forename: Yvonne S
authors.initials: YS
authors.lastname: Lin
mesh_terms: D015415:Biomarkers / Q000097:blood / Q000652:urine; D051544:Cytochrome P-450 CYP3A / Q000187:drug effects / Q000378:metabolism*; D065701:Cytochrome P-450 CYP3A Inducers / Q000494:pharmacology; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology; D055808:Drug Discovery; D004347:Drug Interactions; D006801:Humans; D006854:Hydrocortisone / Q000652:urine*; D006888:Hydroxycholesterols / Q000097:blood* / Q000493:pharmacokinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008874:Midazolam / Q000097:blood*; D008954:Models, Biological
chemical_list: D015415:Biomarkers; D065701:Cytochrome P-450 CYP3A Inducers; D065692:Cytochrome P-450 CYP3A Inhibitors; D006888:Hydroxycholesterols; C099828:cholest-5-ene-3,4-diol; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam; D006854:Hydrocortisone
keywords: 4?-Hydroxycholesterol; CYP3A; biomarker; clinical; drug development; endogenous; induction; inhibition