title: High-dose methotrexate in adult oncology patients: a case-control study assessing the risk association between drug interactions and methotrexate toxicity.
abstract: BACKGROUND
  High-dose methotrexate, defined as dose ≥1 g/m(2), 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, p=0.012) and renal impairment (5 versus 0, p = 0.002). 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 (p = 0.95, 0.59 and 0.20, respectively). Cases experienced more severe anemia (grade 2.52 versus 1.68, p = 0.007) and higher rates of mucositis (65.2% versus 20.0%, p < 0.001).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmacy, London Health Sciences Centre, London, Ontario, Canada.
authors.forename: April J
authors.initials: AJ
authors.lastname: Chan
authors.forename: Irina
authors.initials: I
authors.lastname: Rajakumar
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects*; D016022:Case-Control Studies; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage* / Q000009:adverse effects*; D008875:Middle Aged; D012189:Retrospective Studies
chemical_list: D000964:Antimetabolites, Antineoplastic; D008727:Methotrexate
keywords: High-dose methotrexate; drug interaction; methotrexate clearance; methotrexate toxicity