Hypoalbuminemia is significantly associated with increased clearance time of high dose methotrexate in patients being treated for lymphoma or leukemia

Abstract

As a weak acid, methotrexate (MTX) is bound to serum albumin and has variable protein binding. The purpose of this study was to assess serum albumin’s relationship with MTX pharmacokinetics by comparing MTX clearance and toxicities between patients with normal serum albumin to those with hypoalbuminemia. This single-center retrospective study included adult patients with leukemia or lymphoma who received their first MTX at a dose ≥ 1 gram/m2. Hypoalbuminemia was defined as serum albumin ≤ 3.4 g/dL. MTX clearance was defined as the first documented time the MTX level ≤ 0.05 micromolar. Fisher’s Exact tests and Wilcoxon Rank Sum tests were used to examine differences in toxicities and Cox proportional hazards regression was used to assess relationship with time to clearance. Of 523 patients identified, 167 patients were evaluable. One hundred thirty five patients had normal serum albumin and 32 had hypoalbuminemia. Hypoalbuminemia was associated with a higher proportion of patients experiencing edema, ascites or pleural effusions (34% vs. 12% p=0.006) and the concomitant use of nephrotoxic agents (41% vs. 20% p=0.021). Hypoalbuminemia was associated with a significantly longer time to methotrexate clearance (median: 96 hours vs 72 hour p=0.004). In addition, patients with hypoalbuminemia had a higher proportion of hyperbilirubinemia and significantly longer hospitalization (median 14 days vs. 5 days p<0.001). In conclusion, hypoalbuminemia was associated with increased time to MTX clearance and increase length of hospitalization. High dose MTX is safe to administer in patients with low albumin levels, with appropriate leucovorin rescue and good supportive care.

The effect of asparaginase therapy on methotrexate toxicity and efficacy in children with acute lymphoblastic leukemia

“…MTX is a week acid and binds to serum albumin. Reiss et al have shown that hypoalbuminemia is associated with decreased MTX clearance and an increased length of hospitalization [28]. In our patients, however, the 48 h MTX plasma levels and length of hospitalization did not differ in the patients with and without hypoalbuminemia.…”

MTXPK.org: A Clinical Decision Support Tool Evaluating High‐Dose Methotrexate Pharmacokinetics to Inform Post‐Infusion Care and Use of Glucarpidase

“…Additionally, the NOPHO database had limited covariates to explore. There is considerable interindividual variability in MTX clearance that previous publications have demonstrated to be partially explained by serum albumin, 42 creatinine clearance, 40,43 estimated glomerular filtration rate, 28 concomitant medications, 44 and SLCO1B1 genotype. 18,41,45,46 Furthermore, our PK data did not include information regarding aspects of supportive care, like fluid hydration and urine pH, which can impact MTX clearance.…”

Outcomes in Treatment-Naïve Patients With Metastatic Extremity Osteosarcoma Treated With OGS-12, a Novel Non–High-Dose Methotrexate–Based, Dose-Dense Combination Chemotherapy, in a Tertiary Care Cancer Center

“… 10 , 40 Hypoalbuminemia can increase the clearance time of HDMTX, leading to hyperbilirubinemia and prolonged hospitalization. 41 Lack of facilities for methotrexate level monitoring, high infection rates, underlying malnutrition, and inadequate supportive care facilities make it difficult to administer HDMTX to most of the patients with osteosarcoma in India and other LMICs. In addition, the costs of a protocol incorporating HDMTX are much higher compared with our protocol (Data Supplement).…”