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

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.

Duke Scholars

Author Daniel James George Medicine, Medical Oncology

Author Herbert Ira Hurwitz Medicine, Medical Oncology

Author Andrew John Armstrong Medicine, Medical Oncology