Factors associated with clinically significant systemic methotrexate absorption following intrathecal methotrexate administration - a prospective Study

Abstract

Abstract Intrathecal methotrexate (IT MTX) is a widely used treatment modality for the treatment of hematological malignancies, both as a therapeutic and prophylactic strategy. While this central nervous system targeted treatment is generally considered safe and well-tolerated by patients, there are concerns regarding systemic toxicity following intrathecal administration. Few case reports have described hematological and non-hematological toxic effects following IT MTX. In this prospective study we aim to describe the pharmacokinetics and systemic distribution of IT MTX, and to identify risk factors associated with clinically significant systemic MTX exposure. This study enrolled consecutive patients hospitalized in the Hemato-oncology and Bone Marrow Transplant unit in a large tertiary medical centre and received IT MTX as adjunct to their systemic antineoplastic protocol. Patients who received concomitant systemic MTX administration were excluded. Blood samples for MTX levels were collected at fixed time points; prior to IT MTX administration and +0.5, +1.5, +4, +8, +12, +24, +48 hours following IT MTX administration. Clinical and laboratory factors and their relation to systemic drug levels were analyzed. Twelve patients were recruited to this ongoing clinical trial (Median age 50 years (range 31-77), female n=2). Average GFR was 128 ±45 ml/min and all patients had normal or near-normal GFR values. Of the 12 patients recruited, eleven patients (92%) had serum measurable MTX levels, which began rising as early as half an hour post IT MTX injection, reaching peak values within 4 hours of injection in 10 of 12 patients (83%), with average peak value of 0.48 µmol/L (range 0.07-1.02 µmol/L). Only 3 out of 12 patients (25%) still had detectable serum MTX levels after 24 hours of IT MTX with one patient having detectable levels 48 hours after IT MTX. Risk factors for high systemic MTX levels by ANOVA analysis included third spacing, absence of concurrent proton pump inhibitor (PPI) treatment and ECOG 1 performance status (P=0.004, P=0.048 and, P=0.03, respectively). No clinically relevant toxic sequela was noted for any patient. This ongoing prospective study shows that IT MTX administration is associated with short, rapidly peaking systemic MTX distribution and identifies risk factors for systemic absorption of MTX. Although no significant MTX-associated toxicity was noted in this cohort, these data identify patients at risk for whom prophylactic measures to mitigate potential systemic MTX toxicity after IT administration may be appropriate. This study continues to enroll.