Quantitative Prediction of CYP3A4- and CYP3A5-Mediated Drug Interactions

We verified a physiologically-based pharmacokinetic (PBPK) model to predict cytochrome P450 3A4/5-mediated drug-drug interactions (DDIs). A midazolam (MDZ)-ketoconazole (KTZ) interaction study in 24 subjects selected by CYP3A5 genotype, and liquid chromatography and mass spectroscopy quantification...

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Bibliographic Details
Published inClinical pharmacology and therapeutics Vol. 107; no. 1; p. 246
Main Authors Guo, Yingying, Lucksiri, Aroonrut, Dickinson, Gemma L, Vuppalanchi, Raj K, Hilligoss, Janna K, Hall, Stephen D
Format Journal Article
LanguageEnglish
Published United States 01.01.2020
Subjects
Area Under Curve
Chromatography, Liquid
Cross-Over Studies
Cytochrome P-450 CYP3A - genetics
Dose-Response Relationship, Drug
Drug Interactions
Genotype
Humans
Intestine, Small - metabolism
Ketoconazole - administration & dosage
Ketoconazole - pharmacology
Liver - metabolism
Mass Spectrometry
Midazolam - pharmacokinetics
Models, Biological
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Summary:We verified a physiologically-based pharmacokinetic (PBPK) model to predict cytochrome P450 3A4/5-mediated drug-drug interactions (DDIs). A midazolam (MDZ)-ketoconazole (KTZ) interaction study in 24 subjects selected by CYP3A5 genotype, and liquid chromatography and mass spectroscopy quantification of CYP3A4/5 abundance from independently acquired and genotyped human liver (n = 136) and small intestinal (N = 12) samples, were conducted. The observed CYP3A5 genetic effect on MDZ systemic and oral clearance was successfully replicated by a mechanistic framework incorporating the proteomics-informed CYP3A abundance and optimized small intestinal CYP3A4 abundance based on MDZ intestinal availability (F ) of 0.44. Furthermore, combined with a modified KTZ PBPK model, this framework recapitulated the observed geometric mean ratio of MDZ area under the curve (AUCR) following 200 or 400 mg KTZ, which was, respectively, 2.7-3.4 and 3.9-4.7-fold in intravenous administration and 11.4-13.4 and 17.0-19.7-fold in oral administration, with AUCR numerically lower (P > 0.05) in CYP3A5 expressers than nonexpressers. In conclusion, the developed mechanistic framework supports dynamic prediction of CYP3A-mediated DDIs in study planning by bridging DDIs between CYP3A5 expressers and nonexpressers.
ISSN:1532-6535
DOI:10.1002/cpt.1596