Docetaxel metabolism is not altered by imatinib: findings from an early phase study in metastatic breast cancer

Docetaxel is primarily metabolized by CYP3A4 and susceptible to alterations in clearance by CYP3A4 inhibition and induction. Imatinib is a CYP3A4 inhibitor. A phase I study of docetaxel and imatinib in metastatic breast cancer (MBC) was conducted to test the hypothesis that imatinib decreased docetaxel clearance. Docetaxel was administered weekly x 3 with daily imatinib, repeated every 28 days; during cycle 1, imatinib was started on day 8. Docetaxel and imatinib pharmacokinetics, and hepatic CYP3A4 activity (erythromycin breath test) were evaluated during cycles 1 and 2. Toxicity and efficacy were assessed. Twelve patients were enrolled to three docetaxel/imatinib dose levels: 20 mg/m(2)/600 mg (DL1), 25 mg/m(2)/600 mg (DL2), and 25 mg/m(2)/400 mg (DL2a). Median number of prior chemotherapy regimens was 2 (range, 0-8). Toxicities were primarily observed at DL2; dose-limiting toxicities were Grade 3 transaminase elevations and diarrhea, and 5 patients had grade 2 nausea. Two patients had partial responses (7 months); two stable disease (2 and 4 months); five had progressive disease. Despite a 42% decrease in CYP3A4 activity after 3 weeks of imatinib co-administration, docetaxel clearance was unchanged. Mean +/- A standard deviation steady-state imatinib trough concentration (2.6 +/- A 1.2 mu g/ml) was approximately 2.6-fold higher than previously observed in other cancer populations, and likely contributed to the poor tolerability of the combination in MBC. In conclusion, imatinib inhibited CYP3A4 but did not affect docetaxel clearance. Clinically, further investigation of this combination in MBC is not warranted due to excessive toxicities. However, these unexpected pharmacokinetic findings support further investigation of mechanisms underlying docetaxel elimination pathways.