Impact of pazopanib on docetaxel exposure: Results of a phase I combination study with two different docetaxel schedules
Cancer Chemotherapy and Pharmacology , Volume 75 - Issue 2 p. 365- 371
Purpose: There are several reasons why combining an inhibitor of the vascular endothelial and the platelet-derived growth factor receptor with a taxane might induce synergistic antitumor activity. This phase I study aimed to determine the maximal tolerated dose (MTD) of the combination of pazopanib with two different schedules of docetaxel. Methods: In a 3 + 3 + 3 design, patients with advanced solid tumors received escalating doses of oral pazopanib combined with docetaxel given either every 3 weeks (D3w) or weekly at days 1, 8, and 15 every 28 days (D1w). Pharmacokinetic data of docetaxel and pazopanib were obtained through extensive sampling and WinNonlin modeling. Results: Forty-six patients were enrolled to six dose levels. Both schedules of docetaxel could be combined with 400 mg/day pazopanib. The MTD of D3w docetaxel was 50 mg/m<sup>2</sup>, while for D1w MTD, it was 20 mg/m<sup>2</sup>. In the D3w schedule, the administration of pazopanib led to a 33 % lower docetaxel clearance (mean 31.5 vs 21.1 L/h/m<sup>2</sup>; P = 0.019) and >50 % increase in AUC<inf>0-∞</inf> (mean 1,602 vs 2,414 ng∗h/mL; P = 0.029) compared with docetaxel single-agent data. Data for the D1w schedule were comparable. Conclusions: Both treatment schedules of docetaxel combined with pazopanib are feasible but at doses for both drugs that are considerably lower than the recommended single-agent doses. This is largely due to a clinically relevant pharmacokinetic interaction with pazopanib, substantially increasing docetaxel exposure. This interaction is most likely due to CYP3A4 and OATP1B1 inhibition.