Neurotoxicity and low paclitaxel clearance associated with concomitant clopidogrel therapy in a 60-year-old Caucasian woman with ovarian carcinoma

AimThe aim of the present case report was to describe a novel pharmacokinetic drug-drug interaction between the antiplatelet agent clopidogrel and the antineoplastic agent paclitaxel. MethodsThe patient was identified in a previously described cohort of 93 patients with ovarian carcinoma treated with paclitaxel. The effect of clopidogrel acyl--D-glucuronide on the metabolism of paclitaxel was assessed in human liver microsomes. The analysis of clopidogrel in plasma and the quantification of paclitaxel and 6-hydroxypaclitaxel in in vitro samples were performed by liquid chromatography tandem mass spectrometry. ResultsThe patient was a 60-year-old female treated with an unknown dose of clopidogrel at the time of paclitaxel therapy. Clopidogrel was present in all three of the plasma samples obtained during paclitaxel dosing. Estimated unbound paclitaxel clearance was 238lh(-1), which was only 62% of the cohort geometric mean (385lh(-1); range 176-726). She was hospitalized three times, developed severe neuropathy and paclitaxel treatment was subsequently discontinued. In vitro, 30-min preincubation with 100M clopidogrel acyl--D-glucuronide inhibited the depletion rate of 0.5M paclitaxel by 51% and the formation rate of 6-hydroxypaclitaxel by 77%. ConclusionThis is the first report of a clopidogrel-paclitaxel interaction, suggesting that clinically used doses of clopidogrel can reduce the cytochrome P450 2C8 (CYP2C8)-mediated systemic clearance of paclitaxel, leading to an increased risk of paclitaxel toxicity. Caution should be exercised whenever the simultaneous use of paclitaxel and clopidogrel cannot be avoided.