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

• Authors: Zachary L. Taylor, University of Cincinnati; Tamara Miller, Emory University; Ethan A. Poweleit, University of Cincinnati; Nicholas P. DeGroote, Children's Healthcare of Atlanta; Lauren Pommert, University of Cincinnati; Oluwafunbi Awoniyi, Children's Healthcare of Atlanta; Sarah G. Board, Cincinnati Children's Hospital; Ngozi Ugboh, Children's Healthcare of Atlanta; Vivek Joshi, Children's Healthcare of Atlanta; Nick Ambrosino, Cincinnati Children's Hospital; Ashley Chavana, Baylor College of Medicine; Melanie B. Bernhardt, Baylor College of Medicine; Eric S. Shafer, Baylor College of Medicine; Maureen M. O'Brien, University of Cincinnati; Sharon M. Castellino, Emory University; Laura B. Ramsey, Cincinnati Children's Hospital
• Journal Title: Clinical and Translational Science
• Volume: Volume 16, Number 11
• Publisher: John Wiley and Sons | 2023-08-03, Pages 2130-2143
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1111/cts.13600
• Subjects: Health Sciences, Pharmacology; Health Sciences, Medicine and Surgery
• Keywords: high‐dose methotrexate; acute lymphoblastic leukemia

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.