4β-hydroxycholesterol as an endogenous CYP3A marker in cancer patients treated with taxanes

Abstract

Aim Taxanes are anti-cancer agents used to treat several types of solid tumours. They are metabolized by cytochrome P450 (CYP) 3A, displaying a large pharmacokinetic (PK) variability. In this study, we evaluated the endogenous CYP3A4 marker 4β-hydroxycholesterol (4β-OHC) as a potential individual taxane PK predictor. Methods Serum 4β-OHC and cholesterol concentrations were determined in 291 paclitaxel and 151 docetaxel-treated patients, and were subsequently correlated with taxane clearance. Results In the patients treated with paclitaxel, no clinically relevant correlations between the 4β-OHC or 4β-OHC: cholesterol ratio and paclitaxel clearance were found. In the patients treated with docetaxel, 4β-OHC concentration was weakly correlated with docetaxel clearance in males (r = 0.35 P = 0.01, 95% CI 0.08, 0.58). Of the 10% patients with taxane outlier clearance values, 4β-OHC did correlate with docetaxel clearance in males (r = 0.76, P = 0.03, 95% CI 0.12, 0.95). Conclusion There was no clinical correlation between paclitaxel clearance and the CYP3A4 activity markers 4β-OHC or the 4β-OHC: cholesterol ratio. A weak correlation was observed between 4β-OHC and docetaxel clearance, but only in males. This endogenous CYP3A4 marker has limited predictive value for taxane clearance in patients.