Journal
CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY
Volume 3, Issue 6, Pages -Publisher
WILEY
DOI: 10.1038/psp.2014.18
Keywords
-
Categories
Ask authors/readers for more resources
A Bayesian mechanism-based pharmacokinetic/pharmacodynamic model of cytochrome P450 3A4 (CYP3A4) activity was developed based on a clinical study of the effects of ketoconazole and rifampin on midazolam exposure and plasma 4 beta-hydroxycholesterol (4 beta HC) concentrations. Simulations from the model demonstrated that the dynamic range of 4 beta HC as a biomarker of CYP3A4 induction or inhibition was narrower than that of midazolam; an inhibitor that increases midazolam area under the curve by 20-fold may only result in a 20% decrease in 4 beta HC after 14 days of dosing. Likewise, an inducer that elevates CYP3A4 activity by 1.2-fold would reduce the area under the curve of midazolam by 50% but would only increase 4 beta HC levels by 20% after 14 days of dosing. Elevation in 4 beta HC could be reliably detected with a twofold induction in CYP3A4 activity with study sample sizes (N similar to 6-20) typically used in early clinical development. Only a strong CYP3A4 inhibitor (e.g., ketoconazole) could be detected with similar sample sizes.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available