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

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. One limitation identified during the original development of the MTXPK.org tool was the perceived generalizability since the modeled population comprised solely of Nordic pediatric patients receiving 24-hour infusions for the treatment of acute lymphoblastic leukemia. The goal of our study is to describe the pharmacokinetics of high-dose methotrexate 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 high-dose methotrexate (>0.5 g/m 2 ) 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 high-dose methotrexate, and 30250 concentrations. Our results support the parameterizations of short infusion duration (< 8 hours) 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.