Pharmacokinetic interaction between pazopanib and cisplatin regimen
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A phase I study combining daily oral pazopanib and cisplatin (given iv every 3 weeks) was performed in order to determine the maximum tolerated dose of both drugs in combination. Pharmacokinetic interactions were evaluated.
Plasma pazopanib and ultrafilterable cisplatin concentrations were obtained in 32 patients treated according to four levels of dose corresponding to 200, 400 or 600 mg daily dose of pazopanib and 60 or 75 mg/m2 of cisplatin. Two sequences of treatment were performed in order to explore any interaction of cisplatin on pazopanib pharmacokinetics and inversely. Data were analyzed using the NONMEM program.
Maximum tolerated dose was 400 mg of pazopanib and 75 mg/m2 of cisplatin. Mean (CV % for inter-individual variability) cisplatin clearance was 10.3 L/h (33.2 %) and appeared not to be influenced by pazopanib. However, pazopanib pharmacokinetics was significantly modified by the cisplatin regimen. Mean (CV %) of oral pazopanib clearance was 0.66 L/h (55 %) at Day 0 (before cisplatin administration), 24.8 % lower at Day 1 and 32.9 % lower at Day 2. The interaction is less likely to be due to cisplatin than to a competitive inhibition of pazopanib metabolism and efflux by aprepitant, an antiemetic drug systematically administered with cisplatin. The plasma pazopanib exposures observed at Day 0 with a 400 mg dose were similar to those observed at the recommended dose of pazopanib in monochemotherapy (800 mg) during the first-in-man phase 1 study.
The observed pazopanib plasma overexposure probably contributed to the poor tolerance encountered during this phase 1 study.
KeywordsTyrosine kinase inhibitors Platinum compounds Population pharmacokinetics
The authors wish to thank Dr Melanie White-Koning and Dr Anne Visbecq for their helpful comments on the manuscript.
This work was funded by GlaxoSmithKline and by the charity Ligue Nationale Contre le Cancer.
Compliance with ethical standards
Véronique Diéras discloses advisory board for Novartis and GSK. Thomas Bachelot discloses advisory board and research funding from Novartis, Roche and GSK. Marta Jimenez reports grants and other from GSK, during the conduct of the study. All remaining authors have declared no conflict of interest.
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