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

Abstract

High-dose methotrexate (HDMTX) pharmacokinetics (PKs), including the best estimated glomerular filtration rate (eGFR) equation that reflects methotrexate (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 h postinfusion. MTX and 7-hydroxy-MTX PKs were estimated by standard noncompartmental analysis. Linear regression determined which serum creatinine- or cystatin C-based eGFR equation best predicted MTX clearance. The 80 included patients had a median (interquartile range [IQR]) age of 68.6 years (IQR 59.2-75.6), 54 (67.5%) were men, and 74 (92.5%) were White. The median (IQR) dose of MTX was 7.6 (IQR 4.8-11.3) grams. Median clearance was similar across three dosing levels at 4.5-5.6 L/h and was consistent with linear PKs. 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 fourfold range and appeared to increase in proportion to the dose. The eGFR_cys (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-h infusion displays high interpatient pharmacokinetic variability. Population PK 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.

FIGURE 1

Representative plasma concentration profiles after receipt of HDMTX according to dosing group. The error bars represent the standard deviation for the mean value at each time point. (a) profiles of mean plasma MTX concentrations, (b) profiles of mean plasma 7‐OH‐MTX concentrations. 7‐OH‐MTX, 7‐hydroxy‐methotrexate; HDMTX, high‐dose methotrexate; MTX, methotrexate

FIGURE 2

Area under the time‐curve concentrations of methotrexate. AUC_inf, area under the time curve concentration through infinite time; MTX, methotrexate

FIGURE 3

Correlation between cystatin C‐based estimated glomerular filtration rate (eGFR) equation (ml/min) and clearance of methotrexate (MTX; L/h). (a) Relationship between variables and clearance in the entire cohort, (b) relationship between variables and clearance in a sensitivity analysis that excluded seven patients determine to be outliers