Supportive Care Influence of Concomitant Clopidogrel Consumption on Development of Paclitaxel-Associated Toxicity: A Pharmacoepidemiological Study

Paclitaxel is mainly eliminated via metabolism by the liver enzyme CYP2C8. It has recently been demonstrated in vitro that glucuronidation converts clopidogrel to a metabolite, which is a strong inhibitor of CYP2C8. To determine if this interaction has clinical relevance, we investigated whether concomitant clopidogrel and paclitaxel was associated with severe paclitaxel toxicity, primarily peripheral sensory neuropathy. Patients concomitantly treated with clopidogrel and paclitaxel were identified using treatment registers and the Danish National Database of Reimbursed Prescriptions (DNDRP). Each patient was matched using age and gender with two controls treated with low-dose aspirin and paclitaxel. Paclitaxel induced toxicity was evaluated from medical charts by reviewers partially blinded to clopidogrel exposure. The association of clopidogrel use and development of paclitaxel induced neuropathy was evaluated over accumulated paclitaxel dose with censoring after 1500 mg using Cox-regression analysis with adjustment for high intensity paclitaxel (≥135 mg/m2), performance status, and previous and concomitant chemotherapy. A total number of 7730 patients treated with paclitaxel were screened for having an active clopidogrel prescription. Forty-eight case patients and 88 matching controls with an active aspirin prescription were identified. Median age was 67 years, and 24 % of patients were male. The most frequent cancer types were breast cancer (35% and 30%), ovarian cancer (10% and 17%) in clopidogrel and aspirin users, respectively. At 1500 mg paclitaxel, 20 (42 %) and 27 (31 %) of the patients had developed CTCAE grade 2 neuropathy or worse. Clopidogrel use was associated with increased risk of neuropathy with hazard ratios of 1.7 (95% CI 0.9-3.0), 2.0 (1.0-3.9) and 2.3 (1.1-4.5) in overall unadjusted, high intensity paclitaxel unadjusted and high intensity paclitaxel full adjusted analyses, respectively. Concomitant clopidogrel is associated with increased risk of neuropathy in patients treated with high dose paclitaxel (≥135 mg/m2). Caution should be exercised when combining clopidogrel and paclitaxel.