Clinical covariates that improve the description of high dose methotrexate pharmacokinetics in a diverse population to inform MTXPK.org

Abstract

The MTXPK.org webtool was launched in December 2019 and was developed to facilitate model-informed supportive care and optimal use of glucarpidase following the administration of high-dose methotrexate (HDMTX). One limitation identified during the original development of the MTXPK.org tool was the perceived generalizability because the modeled population comprised solely of Nordic pediatric patients receiving 24-h infusions for the treatment of acute lymphoblastic leukemia. The goal of our study is to describe the pharmacokinetics of HDMTX from a diverse patient population (e.g., races, ethnicity, indications for methotrexate, and variable infusion durations) and identify meaningful factors that account for methotrexate variability and improve the model's performance. To do this, retrospectively analyzed pharmacokinetic and toxicity data from pediatric and adolescent young adult patients who were receiving HDMTX (>0.5 g/m² ) for the treatment of a cancer diagnosis from three pediatric medical centers. We performed population pharmacokinetic modeling referencing the original MTXPK.org NONMEM model (includes body surface area and serum creatinine as covariates) on 1668 patients, 7506 administrations of HDMTX, and 30,250 concentrations. Our results support the parameterizations of short infusion duration (<8 h) and the presence of Down syndrome on methotrexate clearance, the parameterization of severe hypoalbuminemia (<2.5 g/dL) on the intercompartmental clearance (Q2 and Q3), and the parameterization of pleural effusion on the volume of distribution (V1 and V2). These novel parameterizations will increase the generalizability of the MTXPK.org model once they are added to the webtool.

FIGURE 1

Goodness‐of‐fit plots for the final model on the diverse patient data from Cincinnati Children's Hospital Medical Center, Children's Healthcare of Atlanta, and Texas Children's Hospital. Top left, individual predicted concentration versus the observed methotrexate (MTX) concentration. Top right, population predicted concentration versus the observed MTX concentration. Lower left, conditional weighted residual (CWRES) versus the time after start of MTX infusion. Lower right, the CWRES versus the population predicted concentration. Diagonal line in top graphs represent the line of identity. The red line displays the trend for the data. Dotted lines in lower graphs represent the ±2 CWRES. Solid lines in lower graphs represent the ±5 CWRES.

FIGURE 2

Prediction‐corrected visual predictive check for the final model on the diverse patient data from Cincinnati Children's Hospital Medical Center, Children's Healthcare of Atlanta, and Texas Children's Hospital. Methotrexate (MTX) concentrations are represented by the blue circles. The solid red line represents the median MTX concentration for the simulation. The red dashed lines represent the 5th and 95th percentiles for the simulated data. The red shaded region is the median prediction interval. The blue shaded region are the 5% and 95% confidence intervals for the prediction. The deviation of the median prediction interval from the median observed results from delayed MTX elimination, which is often defined as MTX greater than 0.2 μmol/L at 72 h for short infusions and MTX greater than 0.2 μmol/L at 96 h for long infusions. Clinically, MTX measurements cease after it reaching 0.1 μmol/L. As many patients are below this threshold by 96 h, the data for the patients under the median is missing, thus the measured median and the predicted median are different.