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Clinical pharmacology of an atrasentan and docetaxel regimen in men with hormone-refractory prostate cancer

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Abstract

Purpose

This study was conducted to evaluate potential pharmacokinetic interactions between docetaxel and atrasentan as part of a phase I/II clinical trial.

Methods

Patients with prostate cancer were treated with intravenous docetaxel (60–75 mg/m2) every 3 weeks and oral atrasentan (10 mg) daily starting on day 3 of cycle 1 and then given continuously. The pharmacokinetics of both drugs were evaluated individually (cycle 1, day 1 for docetaxel; day 21 for atrasentan) and in combination (cycle 2, day 1 for both drugs). Pharmacogenomics of alpha-1-acid glycoprotein (AAG) were also explored.

Results

Paired pharmacokinetic data sets for both drugs were evaluable in 21 patients. Atrasentan was rapidly absorbed and plasma concentrations varied over a fourfold range at steady state within a typical patient. The median apparent oral clearance of atrasentan was 17.4 L/h in cycle 1 and was not affected by docetaxel administration (p = 0.9). Median systemic clearance of docetaxel was 51.1 L/h on the first cycle and significantly slower (p = 0.01) compared with that obtained during co-administration of atrasentan, 61.6 L/h. Docetaxel systemic clearance in cycle 1 was 70.0 L/h in patients homozygous for a variant allele in AAG compared with 44.5 L/h in those with at least one wild-type allele (p = 0.03).

Conclusion

Genetic polymorphism in AAG may explain some inter-patient variability in docetaxel pharmacokinetics. The systemic clearance of docetaxel is increased by approximately 21 % when given concomitantly with atrasentan; however, atrasentan pharmacokinetics does not appear to be influenced by docetaxel administration.

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Acknowledgments

We wish to acknowledge the patients and Duke Cancer Center Clinical Trials staff for participation in this study. This study was supported in part by an investigator initiated grant from Abbott Pharmaceuticals and NIH Grant 5P20RR016477 to the West Virginia IDeA Network for Biomedical Research Excellence. Dr. Petros also received support as the Mylan Chair of Pharmacology at West Virginia University.

Conflict of interest

None.

Author information

Author notes

  1. Islam R. Younis

    Present address: US FDA, Silver Spring, MD, USA

Authors and Affiliations

  1. Mary Babb Randolph (MBR) Cancer Center, West Virginia University, PO Box 9300, Morgantown, WV, 26506, USA

    Islam R. Younis, Terence J. McManus, Jing Jie Yu, Kristina Bacon & William P. Petros

  2. Department of Basic Pharmaceutical Sciences, West Virginia University, Morgantown, WV, USA

    Islam R. Younis, Cody J. Peer & William P. Petros

  3. Department of Statistics, West Virginia University, Morgantown, WV, USA

    Gerald Hobbs

  4. Duke Prostate Center, Durham, NC, USA

    Daniel J. George, Patricia Creel & Andrew J. Armstrong

  5. Division of Medical Oncology, Department of Medicine, The Duke Comprehensive Cancer Center, Duke University, Durham, NC, USA

    Daniel J. George, Herbert Hurwitz & Andrew J. Armstrong

  6. Division of Urologic Surgery, Department of Surgery, Duke University, Durham, NC, USA

    Daniel J. George, Patricia Creel & Andrew J. Armstrong

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  1. Islam R. Younis
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Correspondence to William P. Petros.

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Younis, I.R., George, D.J., McManus, T.J. et al. Clinical pharmacology of an atrasentan and docetaxel regimen in men with hormone-refractory prostate cancer. Cancer Chemother Pharmacol 73, 991–997 (2014). https://doi.org/10.1007/s00280-014-2432-x

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  • DOI: https://doi.org/10.1007/s00280-014-2432-x

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