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

Abstract

Methotrexate (MTX), an antifolate, is administered at high doses to treat malignancies in children and adults. However, there is considerable interpatient variability in clearance of high-dose (HD) MTX. Patients with delayed clearance are at an increased risk for severe nephrotoxicity and life-threatening systemic MTX exposure. Glucarpidase is a rescue agent for severe MTX toxicity that reduces plasma MTX levels via hydrolysis of MTX into inactive metabolites, but is only indicated when MTX concentrations are > 2 SDs above the mean excretion curve specific for the given dose together with a significant creatinine increase (> 50%). Appropriate administration of glucarpidase is challenging due to the ambiguity in the labeled indication. A recent consensus guideline was published with an algorithm to provide clarity in when to administer glucarpidase, yet clinical interpretation of laboratory results that do not directly correspond to the algorithm prove to be a limitation of its use. The goal of our study was to develop a clinical decision support tool to optimize the administration of glucarpidase for patients receiving HD MTX. Here, we describe the development of a novel 3-compartment MTX population pharmacokinetic (PK) model using 31,672 MTX plasma concentrations from 772 pediatric patients receiving HD MTX for the treatment of acute lymphoblastic leukemia and its integration into the online clinical decision support tool, MTXPK.org. This web-based tool has the functionality to utilize individualized demographics, serum creatinine, and real-time drug concentrations to predict the elimination profile and facilitate model-informed administration of glucarpidase.

Figure 1

Concentration‐time plot of the Nordic Society for Pediatric Hematology and Oncology dataset. Individual concentrations are in blue with a box and whiskers plot shown on top. The black line represents the median value. The box plot illustrates the interquartiles with the whiskers representing the two SDs.

Figure 2

Comparing the goodness‐of‐fit plots for two‐compartment and three‐compartment structural models. The three‐compartment model showed significantly less bias at lower predicted concentrations (a) compared to the two‐compartment model (b), which displayed overestimation of clearance. The three‐compartment model displayed improved predictive performance at later times following a methotrexate (MTX) infusion (c) compared with the two‐compartment model (d). A total of 1,494 weighted residuals (4.7%) were found outside of ± 2 conditional weighted residuals (CWRES). The CWRES displayed a normal distribution with 649 residuals below −2. For a and b, the dotted line represents the line of identity. For c and d, the dotted line represents the zero‐line. The dashed lines represent the two SDs. The solid black line represents the trend line for all figures.

Figure 3

Covariate analysis. The coefficient of determination for body surface area (BSA) and the estimated clearance (a, R ² = 0.54) is a stronger relationship than the coefficient of determination for weight allometrically scaled to 70 kg and the estimated clearance (b, R ² = 0.25). Serum creatinine demonstrated a nonlinear with clearance normalized to BSA (c). The gray dots represent clearance estimates at the first serum creatinine level for each patient course.

Figure 4

Screenshots of MTXPK.org. (a) Patient demographics are easily loaded into the “Patient Data and Dosing” screen. Plasma methotrexate (MTX) concentrations and serum creatinine levels are added to the “Measurements” tab (b). After hitting “Calculate,” the individualized pharmacokinetic (PK) estimates and concentration‐time curve are generated (c). With the use of MTXPK.org, the user would conclude that this patient would meet the indication for glucarpidase because the individualized PK elimination curve (black line) is higher than the elimination curve for the population (green line), the two SDs (red line), and is close to the concentrations outline by the glucarpidase guideline (purple diamonds). The full concentration‐time curve for the example patient (d) demonstrates the accurate forecasting of plasma MTX concentrations. AUC, area under the elimination curve.