Clinical pharmacology of an atrasentan and docetaxel regimen in men with hormone-refractory prostate cancer |
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Authors: | Islam R. Younis Daniel J. George Terence J. McManus Herbert Hurwitz Patricia Creel Andrew J. Armstrong Jing Jie Yu Kristina Bacon Gerald Hobbs Cody J. Peer William P. Petros |
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Affiliation: | 1. Mary Babb Randolph (MBR) Cancer Center, West Virginia University, PO Box 9300, Morgantown, WV, 26506, USA 2. Department of Basic Pharmaceutical Sciences, West Virginia University, Morgantown, WV, USA 7. US FDA, Silver Spring, MD, USA 4. Duke Prostate Center, Durham, NC, USA 5. Division of Medical Oncology, Department of Medicine, The Duke Comprehensive Cancer Center, Duke University, Durham, NC, USA 6. Division of Urologic Surgery, Department of Surgery, Duke University, Durham, NC, USA 3. Department of Statistics, West Virginia University, Morgantown, WV, USA
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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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