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Introduction: High-dose methotrexate, defined as dose ≥1 g/m2, is commonly used in chemotherapy protocols. Certain drugs such as acyclovir, allopurinol, proton pump inhibitors and some antibiotics have been associated with delayed renal clearance of methotrexate and may predispose patients to toxicities. Currently, no specific recommendations exist on adjusting the high-dose methotrexate regimen in the presence of potential interacting drugs. This study aims to determine whether presence of interacting drugs is associated with delayed methotrexate clearance. Methods: This was a case-control study of adult oncology patients who received their first cycle of high-dose methotrexate. Cases were defined as patients who experienced delayed methotrexate clearance, as indicated by serum methotrexate level≥0.1 umol/L at 72 h. The primary endpoint was the frequency of presence of interacting drugs between cases and controls. These were compared using Fisher’s exact test. Where possible, adjustment for significant baseline differences that can affect methotrexate clearance was made using logistic regression. The secondary endpoint was frequency of methotrexate-related clinical toxicities between groups and included myelosuppression, nephrotoxicity, hepatotoxicity and mucositis. Results: From January 2004 to March 2011, 73 patients met study criteria, of which 23 were defined as cases. Significant baseline differences were methotrexate dose received (9116 mg±4339 versus 6054 mg±2874, p¼0.012) and renal impairment (5 versus 0, p¼0.002). The presence of interacting drugs was not associated with delayed methotrexate clearance (OR 0.91, 95% CI 0.24–3.38, p>0.999). After adjusting for methotrexate dose, drugs observed more frequently (allopurinol, proton pump inhibitors and sulfamethoxazole/trimethoprim) were not associated with delayed methotrexate clearance (p¼0.95, 0.59 and 0.20, respectively). Cases experienced more severe anemia (grade 2.52 versus 1.68, p¼0.007) and higher rates of mucositis (65.2% versus 20.0%, p<0.001). Conclusion: This study showed no significant association between presence of interacting drugs and delayed methotrexate clearance. Patients who experienced delayed methotrexate clearance had higher incidence of severe anemia and mucositis. [ABSTRACT FROM AUTHOR]