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Pharmacologic and phenotypic study of docetaxel in patients with ovarian or primary peritoneal cancer

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Abstract

Purpose

The objectives of this study were to determine whether the midazolam clearance predicted docetaxel pharmacokinetics, CA-125 change, and response and to assess the impact of cytochrome P450 (CYP) 3A5 and ATP-binding cassette, subfamily B, member 1 (ABCB1) genotypes on docetaxel pharmacokinetics and pharmacodynamics in ovarian or primary peritoneal cancer patients.

Methods

Thirty-four patients with advanced ovarian and primary peritoneal cancer were administered docetaxel at 75 mg/m2 as a 1-h infusion in combination with carboplatin IV over 30 min at a target AUC of 5 mg/ml min. Cycles were repeated every 21 days for 6 cycles. Midazolam was administered at 2 mg as a 30-min IV infusion the day prior to cycle one of docetaxel administration. Pharmacokinetic studies of docetaxel and CYP3A5 and ABCB1 genotype studies were performed.

Results

There was an inverse relationship between midazolam clearance (CL) and CA-125 level after cycle 6 where a higher midazolam CL was associated with a CA-125 <10 U/ml (P = 0.007) and CA-125 <15 U/ml (P = 0.048). The CA-125 categories were associated with response achieved (complete response/partial response) (CR/PR), stable disease (SD), and progressive disease (PD) at the end of therapy (P = 0.0173). Docetaxel CL was not related to midazolam CL or genotype. Docetaxel exposure and genotypes were not related to toxicity or response (P > 0.05).

Conclusions

The midazolam CL predicted CA-125 levels and response that was independent of other factors including docetaxel pharmacokinetics. Future studies need to evaluate the mechanism for the relationship between midazolam CL and response in patients with ovarian cancer.

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Conflict of interest

Research funding was provided by Sanofi-Aventis Oncology.

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Authors and Affiliations

  1. Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, 1013 Genetic Medicine Building, CB 7361, Chapel Hill, NC, 27599, USA

    William C. Zamboni, Austin J. Combest, Christine M. Walko & Angela Y. C. Yu

  2. UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA

    William C. Zamboni & Christine M. Walko

  3. Carolina Center of Cancer Nanotechnology Excellence, Chapel Hill, NC, 27599, USA

    William C. Zamboni

  4. Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27598, USA

    William C. Zamboni & Christine M. Walko

  5. North Carolina Biomedical Innovation Network, Chapel Hill, NC, USA

    William C. Zamboni

  6. Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, Magee Womens Research Institute, Pittsburgh, PA, 15213, USA

    Julie A. DeLoia, Robert P. Edwards, Thomas C. Krivak & Joseph L. Kelley

  7. Department of Pathology, UNC School of Medicine, Chapel Hill, NC, 27599, USA

    Arlene S. Bridges

  8. Department of Mathematics, Carlow University, Pittsburgh, PA, 15213, USA

    Beth A. Zamboni

Authors
  1. William C. Zamboni
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  2. Austin J. Combest
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  3. Julie A. DeLoia
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  4. Robert P. Edwards
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  5. Arlene S. Bridges
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  6. Beth A. Zamboni
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  7. Christine M. Walko
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  8. Angela Y. C. Yu
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  9. Thomas C. Krivak
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  10. Joseph L. Kelley
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Corresponding author

Correspondence to William C. Zamboni.

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Zamboni, W.C., Combest, A.J., DeLoia, J.A. et al. Pharmacologic and phenotypic study of docetaxel in patients with ovarian or primary peritoneal cancer. Cancer Chemother Pharmacol 68, 1255–1262 (2011). https://doi.org/10.1007/s00280-011-1609-9

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  • DOI: https://doi.org/10.1007/s00280-011-1609-9

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