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 anti-folate, 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 standard deviations 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 lab 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 three-compartment MTX population 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.

Systematic Review of Pharmacogenetic Factors That Influence High-Dose Methotrexate Pharmacokinetics in Pediatric Malignancies

“…PK findings from clinical studies can lead to improvements in therapeutic outcomes through amendments to clinical protocols [ 5 , 15 ] or the development of clinical decision support tools [ 16 ]. It was recently shown that >90% of persons have an actionable drug-gene polymorphism [ 17 , 18 ].…”

Creation of an inventory of quality markers used to evaluate pharmacokinetic literature: A systematic review

“…A total of 17 papers were included for extraction of quality markers. Articles included two original article about assessing the quality of reporting of clinical pharmacokinetics studies, 6,9 one systematic review, 10 one mini-review, 11 two organizational reports, 12,13 nine reviews [14][15][16][17][18][19][20][21][22] and two guidelines. 23,24 The included articles discussed the quality markers pertaining to retrospective and prospective clinical pharmacokinetic studies, bioequivalence studies, as well as population pharmacokinetic studies.…”

The Changing Face of Oncology Research, Drug Development, and Clinical Practice: Toward Patient‐Focused Precision Therapeutics

“…14 Whereas these examples are illustrative of hypothesis generation for TDM, equally crucial for clinical translation are innovations in model-informed clinical decision support systems for deployment of TDM and downstream patient management in clinical practice. 15 Physiologically-based pharmacokinetic modeling and simulation has steadily driven efficiency in evaluating intrinsic and extrinsic factor effects in drug development to inform dosing and administration across clinical contexts of use, as elegantly demonstrated with the cyclin-dependent kinase 4/6 inhibitor ribociclib. 16 Of note, our understanding of sources of variability in the clinical pharmacology of therapeutics continues to evolve, illustrated in a survey of the impact of hepatic impairment on pharmacokinetics of monoclonal antibodies.…”