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 × 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 ± standard deviation steady-state
imatinib trough concentration (2.6 ± 1.2 μg/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.