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- Title
Validation of 4β-hydroxycholesterol and evaluation of other endogenous biomarkers for the assessment of CYP3A activity in healthy subjects.
- Authors
Kasichayanula, Sreeneeranj; Boulton, David W.; Luo, Wen‐Lin; Rodrigues, A. David; Yang, Zheng; Goodenough, Angela; Lee, Michelle; Jemal, Mohammed; LaCreta, Frank
- Abstract
AIMS This study aimed to assess changes in the plasma concentrationss of 4ß-hydroxycholesterol (4ßHC) against intravenous (i.v.) and oral midazolam (MDZ) pharmacokinetics (PK) after administration of a potent CYP3A inhibitor [ketoconazole (KETO)] and inducer [rifampicin (RIF)]. METHODS Thirty-two healthy subjects (HS) were allocated into three groups of 12 each in KETO and RIF and 10 in a placebo group (PLB). All HS were randomized to receive oral and i.v. MDZ on day 1 or 2 and on day 15 or 16 after receiving RIF (600 mg once daily), KETO (400 mg once daily) or PLB for 2 weeks. Subjects were followed until day 30. The effect of treatments on 4ßHC was assessed by analyzing % change from baseline using a linear spline mixed effects model. RESULTS Compared with PLB, KETO decreased 4ßHC mean values up to 13% (P = 0.003) and RIF increased 4ßHC mean values up to 220% (P < 0.001). Within 14 days of stopping KETO and RIF, 4ßHC had either returned to baseline (KETO) or was still returning to baseline (RIF). Compared with baseline, mean oral MDZ AUC increased by 11-fold (90% CI ranging from 9-fold to 13-fold increase) and decreased by 92% (90% CI ranging from 90% to 95% decrease) after KETO and RIF, respectively. Similar trends were observed for 6ß-hydroxycortisol :cortisol (6ßHCL:CL) urinary ratios. CONCLUSIONS Changes in plasma 4ßHC can be utilized as a surrogate for MDZ PK after multiple doses of potent CYP3A inducers. There is a more limited dynamic range for 4ßHC for assessment of potential CYP3A inhibitors. 4ßHC is a valuable tool for the assessment of potential CYP3A inducers in early drug development.
- Subjects
HYDROXYCHOLESTEROLS; MIDAZOLAM; METABOLIC clearance rate; KETOCONAZOLE; RIFAMPIN
- Publication
British Journal of Clinical Pharmacology, 2014, Vol 78, Issue 5, p1122
- ISSN
0306-5251
- Publication type
Article
- DOI
10.1111/bcp.12425