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

Details

• Personal Author:
  Armstrong AJ ; Bacon K ; Creel P ; George DJ ; Hobbs G ; Hurwitz H ; McManus TJ ; Peer CJ ; Petros WP ; Younis IR ; Yu JJ
• Description:
  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/m(2)) 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. [Description provided by NIOSH]
• Subjects:
  Drug Therapy Genetics Men Neoplasms Occupational Health Safety
• Keywords:
  Author Keywords: Atrasentan Cancer Docetaxel Drugs Drug Therapy Humans Pharmacogenomics Pharmacokinetics Pharmacology Prostate Cancer
• ISSN:
  0344-5704
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Journal Article
• Place as Subject:
  North Carolina ; OSHA Region 3 ; OSHA Region 4 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  73
• Issue:
  5
• NIOSHTIC Number:
  nn:20049502
• Citation:
  Cancer Chemother Pharmacol 2014 May; 73(5):991-997
• Contact Point Address:
  William P. Petros, Pharm.D., FCCP, West Virginia University/MBR Cancer Center, PO Box 9300, Morgantown, WV 26506
• Email:
  wpetros@hsc.wvu.edu
• CAS Registry Number:
  Atrasentan (CAS RN 173937-91-2) ; Docetaxel (CAS RN 114977-28-5)
• Federal Fiscal Year:
  2014
• Performing Organization:
  West Virginia University
• Peer Reviewed:
  False
• Start Date:
  20050701
• Source Full Name:
  Cancer Chemotherapy and Pharmacology
• End Date:
  20250630
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:bfce8a893811958ab2be3fe73d925c96cc460938b55d304982bda7fee1665bdffb824dae1dfba907f58b65591f6b191913ca47363c943ed71154db7fef8ce5e2
• Download URL:
  https://stacks.cdc.gov/view/cdc/203942/cdc_203942_DS1.pdf
• File Type:
  [PDF - 305.87 KB ]