PT  - JOURNAL ARTICLE
AU  - Takubo, Hiroaki
AU  - Taniguchi, Toshio
AU  - Nomura, Yukihiro
TI  - Quantitative Prediction of Drug-Drug Interactions Caused by CYP3A Induction Using Endogenous Biomarker 4<em>β</em>-Hydroxycholesterol
AID  - 10.1124/dmd.124.001876
DP  - 2024 Dec 01
TA  - Drug Metabolism and Disposition
PG  - 1438--1444
VI  - 52
IP  - 12
4099  - http://dmd.aspetjournals.org/content/52/12/1438.short
4100  - http://dmd.aspetjournals.org/content/52/12/1438.full
SO  - Drug Metab Dispos2024 Dec 01; 52
AB  - Evaluation of the CYP3A induction risk is important in early drug development stages. This study focused on 4β-hydroxycholesterol (4β-HC) as an endogenous biomarker of drug-drug interactions (DDIs) caused by CYP3A induction. We investigated a new approach using 4β-HC for quantitative prediction of DDIs caused by CYP3A induction based on the mechanistic static pharmacokinetic (MSPK) model. The induction ratio, i.e., the ratio of plasma 4β-HC or 4β-HC/cholesterol (4β-HC/C) with and without a coadministered CYP3A inducer, and the ratio of the area under the plasma concentration-time curve (AUCR), i.e., the ratio of the AUC of plasma CYP3A substrate drugs with and without a coadministered CYP3A inducer, were collected. The scaling factor (d) in the MSPK model was calculated from the induction ratio of 4β-HC or 4β-HC/C based on the systemic term in the MSPK model. The AUCR of 18 CYP3A substrates with and without coadministration of seven CYP3A inducers were then predicted by substituting the calculated d value into the MSPK model. This approach showed that approximately 84% of the predicted AUCR values were within a twofold range of the observed values, showing that this approach can be a good tool to quantitatively predict DDIs caused by CYP3A induction.SIGNIFICANCE STATEMENT A concise approach to predict drug interactions with adequate accuracy is preferable in the early drug development stage. In this study, a new approach using 4β-hydroxycholesterol for quantitative prediction of drug-drug interactions caused by CYP3A induction was investigated. The predictability was verified using seven CYP3A inducers and 18 substrates.