Impact of paclitaxel on pazopanib pharmacokinetics in patients with ovarian cancers from phase II trial TAPAZ

Background: Combining standard chemotherapy with anti-angiogenic agents could improve efficacy in platinum-resistant recurrent ovarian cancer but is associated with increased toxicity, possibly due to pharmacokinetic (PK) interactions. The objective was to evaluate the impact of paclitaxel on pazopanib PK, and the relationship between toxicity and pazopanib PK in recurrent ovarian cancer patients enrolled in TAPAZ (Paclitaxel/ Pazopanib for Platinum Resistant/ Refractory Ovarian Cancer) study. Methods: TAPAZ randomized phase II trial assessed the efficacy and toxicity of the standard weekly paclitaxel 80 mg/m2 (P arm) with respect to those of an experimental arm composed of weekly paclitaxel 65 mg/m2 combined to pazopanib 600–800 mg daily (PP arm) in recurrent ovarian cancer patients. PK sampling was performed during cycle 1 in patients from PP arm. Pazopanib PK data was analysed using non-linear mixed effects modelling. Results: The study enrolled 116 patients (n = 79 in PP arm, n = 39 in P arm). Pazopanib PK data were available in 56 patients from PP arm. Co-administration of paclitaxel resulted in a decrease in relative bioavailability of pazopanib (mean decrease: −18.8%, 95% CI (Confidence Interval) = −36.6%; +15.0%), without significant impact on area-under-the-concentration-time curve (p = 0.50). During cycle 1, pazopanib dose-limiting toxicity was observed in 23% of patients from PP arm, and was not correlated with pazopanib plasma exposure (p = 0.26). Conclusions: The present ancillary study of TAPAZ trial showed that paclitaxel does not significantly impact plasma pazopanib exposure. The exacerbated toxicity observed in the combination arm with lower paclitaxel dose could not be explained by increased pazopanib plasma exposure due to a PK drug-drug interaction. Clnical Trial Registration: NCT02383251.

Ovarian neoplasms; Paclitaxel; Pazopanib; Pharmacokinetics; Pharmacodynamics; Drug-drug interactions

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