Comparative Pharmacokinetics of Weekly and Every-Three-Weeks Docetaxel

Purpose: Weekly administration of docetaxel has demonstrated comparable efficacy together with a distinct toxicity profile with reduced myelosuppression, although pharmacokinetic data with weekly regimens are lacking. The comparative pharmacokinetics of docetaxel during weekly and once every 3 weeks (3-weekly) administration schedules were evaluated. Experimental Design: Forty-six patients received weekly docetaxel (35 mg/m²) as a 30-min infusion alone (n = 8) or in combination with irinotecan (n = 12), or in 3-weekly regimens, as a 1-h infusion at 60 mg/m² with doxorubicin (n = 10), 75 mg/m² alone (n = 9), or 100 mg/m² alone (n = 7). Serial blood samples were obtained immediately before and up to 21 days after the infusion. Plasma concentrations were measured by liquid chromatography-mass spectrometry and analyzed by compartmental modeling. Results: Mean ± SD docetaxel clearance values were similar with weekly and 3-weekly schedules (25. 2 ± 7.7 versus 23.7 ± 7.9 liter/h/m²); half-lives were also similar with both schedules of administration (16.5 ± 11.2 versus 17.6 ± 7.4 h). With extended plasma sampling beyond 24 h post-infusion, docetaxel clearance was 18% lower and the terminal half-life was 5-fold longer. At 35 mg/m², the mean ± SD docetaxel concentration on day 8 was 0.00088 ± 0.00041 μg/ml (1.08 ± 0.51 nM) at 75 mg/m ², concentrations on day 8, 15, and 22 were 0.0014 ± 0.00043 μg/ml (1.79 ± 0.53 nM), 0.00067 ± 0.00025 μg/ml (0.83 ± 0.31 nM), and 0.00047 ± 0.00008 μg/ml (0.58 ± 0.099 nM), respectively. Conclusion: Docetaxel pharmacokinetics are similar for the weekly and 3-weekly regimens. Prolonged circulation of low nanomolar concentrations of docetaxel may contribute to the mechanism of action of docetaxel through suppression of microtubule dynamics and tumor angiogenesis and enhanced cell radiosensitivity in combined modality therapy.