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

  • Br J Clin Pharmacol. 2015 Sep;80(3):560-8. doi: 10.1111/bcp.12707.
Anne-Joy M de Graan  1 ,  Alex Sparreboom  1  2 ,  Peter de Bruijn  1 ,  Evert de Jonge  3 ,  Bronno van der Holt  4 ,  Erik A C Wiemer  1 ,  Jaap Verweij  1 ,  Ron H J Mathijssen  1 ,  Ron H N van Schaik  3
Affiliations
  • 1. Department of Medical Oncology, Erasmus MC Cancer Institute, 's-Gravendijkwal 230, 3015CE, Rotterdam.
  • 2. Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, 262 Danny Thomas Place, 38105-3678, Memphis, TN, USA.
  • 3. Department of Clinical Chemistry, Erasmus University Medical Center, 's-Gravendijkwal 230, 3015CE, Rotterdam, the Netherlands.
  • 4. Department of Trials and Statistics, Erasmus University Medical Center, 's-Gravendijkwal 230, 3015CE, Rotterdam, the Netherlands.
PMID: 26119961 DOI: 10.1111/bcp.12707
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.

Keywords
4β-hydroxycholesterol; CYP3A activity; endogenous marker; pharmacokinetics; taxanes.
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