Background and importance High dose methotrexate (HDMTX) chemotherapy, defined as a dose >500 mg/m², is used to treat several oncological and haematological malignancies. Despite appropriate hydration, urine alkalisation and leucovorin rescue, nephrotoxicity remains a risk which can lead to significant morbidity and mortality. Different drugs have been associated with altered elimination (AE) of HDMTX due to delayed elimination or nephrotoxicity.

Aim and objectives To describe the incidence of AE and assess the impact of drug interactions in HDMTX induced AE.

Material and methods A bibliographic research in the Lexicomp database was conducted to identify drug interactions with HDMTX. A retrospective study was carried out including all patients who received HDMTX between 2010 and 2019. Data collected were age, sex, methotrexate dosage, number of HDMTX cycles, creatinine level before and after HDMTX, serum levels of methotrexate and potentially interacting medications (PIM) prescribed 24 hours before HDMTX infusion and during methotrexate elimination. AE was defined as plasma concentration >1 μmol/L at 48 hours and/or 0.1 μmol/L at 72 hours, or nephrotoxicity according to the Common Terminology Criteria for Adverse Events criteria V.4.0.

The association of PIM with AE was determined by OR and the χ² test or Fisher’s exact probability test.

Results Sixty-four patients were treated with HDMTX for 160 cycles with a median HDMTX dose of 11760 mg (IQR 3370–14 207.5 mg). Median age was 66.4 years (IQR 55.6–75.3) and 42.2% were women. Eleven patients were treated for leukaemia and 53 for lymphoma.

Median baseline creatinine was 0.66 (IQR 0.57–0.78) mg/dL. AE was present in 80 cycles (50%). In 91.3% of these, patients were receiving concomitant PIM with methotrexate elimination. In 52 cycles methotrexate elimination was altered only after 72 hours.

PIM associated with AE were: levetiracetam (OR=6.9, 95% CI 1.5–32.4; p<0.05), non-steroidal anti-inflammatory drugs (OR=10.9, 95% CI 2.4–49.4; p<0.05) and doxycycline (OR=0.5, 95% CI 0.4–0.6; p<0.05). There were no significant differences between use of proton pump inhibitors, loop diuretics, amphotericin B, penicillin and derivate, aminoglycosides, ciprofloxacin or p-glycoprotein/ABCB1 inhibitors.

Conclusion and relevance There was a high prevalence of patients with AE of HDMTX. Potentially interacting medications with HDMTX are frequently used during treatment. Only levetiracetam and non-steroidal anti-inflammatory drugs were associated with methotrexate AE in our patients.

References and/or acknowledgements No conflict of interest.