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Leil TA, Kasichayanula S, Boulton DW, et al. Evaluation of 4β-Hydroxycholesterol as a Clinical Biomarker of CYP3A4 Drug Interactions Using a Bayesian Mechanism-Based Pharmacometric Model. CPT Pharmacometrics Syst Pharmacol. 2014;3:e120doi: 10.1038/psp.2014.18.
Leil, T. A., Kasichayanula, S., Boulton, D. W., & LaCreta, F. (2014). Evaluation of 4β-Hydroxycholesterol as a Clinical Biomarker of CYP3A4 Drug Interactions Using a Bayesian Mechanism-Based Pharmacometric Model. CPT: pharmacometrics & systems pharmacology, 3e120. https://doi.org/10.1038/psp.2014.18
Leil, T A, et al. "Evaluation of 4β-Hydroxycholesterol as a Clinical Biomarker of CYP3A4 Drug Interactions Using a Bayesian Mechanism-Based Pharmacometric Model." CPT: pharmacometrics & systems pharmacology vol. 3 (2014): e120. doi: https://doi.org/10.1038/psp.2014.18
Leil TA, Kasichayanula S, Boulton DW, LaCreta F. Evaluation of 4β-Hydroxycholesterol as a Clinical Biomarker of CYP3A4 Drug Interactions Using a Bayesian Mechanism-Based Pharmacometric Model. CPT Pharmacometrics Syst Pharmacol. 2014 Jun 25;3:e120. doi: 10.1038/psp.2014.18. PMID: 24964282; PMCID: PMC4076805.
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CPT Pharmacometrics Syst Pharmacol. 2014 Jun 25;3:e120. doi: 10.1038/psp.2014.18.

Evaluation of 4β-Hydroxycholesterol as a Clinical Biomarker of CYP3A4 Drug Interactions Using a Bayesian Mechanism-Based Pharmacometric Model.

CPT: pharmacometrics & systems pharmacology

T A Leil, S Kasichayanula, D W Boulton, F LaCreta

Affiliations

  1. Exploratory Clinical & Translational Research, Bristol-Myers Squibb Company, Lawrenceville, New Jersey, USA.

PMID: 24964282 PMCID: PMC4076805 DOI: 10.1038/psp.2014.18

Abstract

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 4β-hydroxycholesterol (4βHC) concentrations. Simulations from the model demonstrated that the dynamic range of 4βHC 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 4βHC 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 4βHC levels by 20% after 14 days of dosing. Elevation in 4βHC could be reliably detected with a twofold induction in CYP3A4 activity with study sample sizes (N ~ 6-20) typically used in early clinical development. Only a strong CYP3A4 inhibitor (e.g., ketoconazole) could be detected with similar sample sizes.

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