Plasma 4β-Hydroxycholesterol Predicts Ribociclib CYP3A-Mediated Metabolism, but Not Plasma Exposure, in Patients with Primary Brain Cancer

Background/Objectives: This study aimed to evaluate the potential utility of plasma 4β-hydroxycholesterol (4β-OHC) as an endogenous biomarker of hepatic CYP3A activity for predicting ribociclib metabolism and systemic pharmacokinetics in patients with primary brain cancer. Methods: Plasma concentration data for ribociclib and its major metabolite, LEQ803, were obtained from 46 patients receiving oral ribociclib at daily doses of 400, 600, or 900 mg for 5 days. Plasma 4β-OHC concentrations and 4β-OHC/cholesterol ratios were determined by LC–MS/MS at baseline and at 4 and 24 h after ribociclib administration on day 5. A parent–metabolite population pharmacokinetic model was developed to simultaneously characterize ribociclib and LEQ803 disposition and identify clinical covariates influencing their pharmacokinetics. Results: The parent–metabolite model adequately described the multiple-dose plasma concentration–time profiles of ribociclib and LEQ803. On-treatment plasma 4β-OHC concentration was identified as a significant predictor for CYP3A-mediated ribociclib metabolism to LEQ803, accounting for ~36% of interindividual variability in the metabolic clearance. Plasma 4β-OHC showed limited ability to predict total apparent oral clearance or systemic exposure of ribociclib. Conclusions: These findings support the clinical utility of plasma 4β-OHC as an endogenous biomarker of hepatic CYP3A activity for predicting CYP3A-mediated metabolism of substrate drugs such as ribociclib, while highlighting its limitation for predicting total apparent oral clearance of drugs undergoing intestinal first-pass metabolism and elimination through multiple pathways. These results underscore the importance of considering the relative contribution of hepatic CYP3A metabolism to overall drug disposition when evaluating translational utility of endogenous CYP3A biomarkers in clinical pharmacology.