Propsective evaluation of high-dose methotrexate pharmacokinetics in adult patients with lymphoma using novel determinants of kidney function.

High-dose methotrexate (HDMTX) pharmacokinetics, including the best estimated glomerular filtration rate (eGFR) equation that reflects MTX clearance, requires investigation. This prospective, observational, single-center, study evaluated adult patients with lymphoma treated with HDMTX. Samples were collected at predefined time points up to 96 hours post-infusion. Methotrexate (MTX) and 7-hydroxy-MTX pharmacokinetics were estimated by standard non-compartmental analysis. Linear regression determined which serum creatinine- or cystatin C-based eGFR equation best predicted MTX clearance. The 80 included patients had a median (IQR) age of 68.6 years (59.2, 75.6), 54 (67.5%) were male, and 74 (92.5%) were White. The median (IQR) dose of MTX was 7.6 (4.8, 11.3) grams. Median clearance was similar across three dosing levels at 4.5 to 5.6 L/hr and was consistent with linear pharmacokinetics. Liver function, weight, age, sex, concomitant chemotherapy, and number of previous MTX doses did not impact clearance. MTX area under the curve (AUC) values varied over a 4-fold range and appeared to increase in proportion to the dose. The eGFRcys (mL/min) equation most closely correlated with MTX clearance in both the entire cohort and after excluding outlier MTX clearance values (r = 0.31 and 0.51, respectively). HDMTX as a 4-hour infusion displays high interpatient pharmacokinetic variability. Population pharmacokinetic modeling to optimize MTX AUC attainment requires further evaluation. The cystatin C-based eGFR equation most closely estimated MTX clearance and should be investigated for dosing and monitoring in adults requiring MTX as part of lymphoma management.