title: Evaluating performance of a decision support system to improve methotrexate pharmacotherapy in children and young adults with cancer.
abstract: The management of high-dose methotrexate (MTX) therapy in patients with cancer depends on the routine monitoring of drug exposures in conjunction with leucovorin (LV), urine pH, patient hydration, and other clinical indices of patient well-being. A key factor in patient oversight is the facilitation of MTX clearance to minimize drug-related toxicity. The aim of this investigation was to evaluate the performance of a clinical decision support system and Bayesian forecasting algorithm in the prediction of MTX concentrations and assessment of LV dosing requirements in pediatric and young adult patients with cancer based on the current practice at the Children's Hospital of Philadelphia. Fifty patients ranging in age from 8 months to 21 years (weight range, 7.6-163.3 kg) contributing 80 total dosing events (183 MTX serum concentrations) were studied. The forecasting model was able to consistently predict future MTX concentrations with the knowledge of one prior concentration and continued to improve with additional concentration data made available through daily therapeutic drug monitoring. Precision was good at 12.9% with low bias at 2.2%. Comparison between the decision support system recommendations for LV rescue relative to the actual LV administration was also made. Sixteen patients would have initiated rescue therapy earlier, seven patients would have received a larger dose (42 smaller), and LV would have been given less often for 37 patients. The forecasting algorithm in the MTX dashboard was reasonably accurate in predicting MTX concentrations and should improve further as the underlying model and prediction algorithm evolves. This decision support system can be useful in helping physicians decide if a patient is clearing MTX as expected or if more aggressive rescue therapy is warranted.
authors.affiliation: Laboratory for Applied PK/PD, Division of Clinical Pharmacology & Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: Dombrowsky
authors.forename: Bhuvana
authors.initials: B
authors.lastname: Jayaraman
authors.forename: Mahesh
authors.initials: M
authors.lastname: Narayan
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Barrett
mesh_terms: D000293:Adolescent; D000328:Adult; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001499:Bayes Theorem; D002648:Child; D002675:Child, Preschool; D020000:Decision Support Systems, Clinical; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D007223:Infant; D002955:Leucovorin / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D008727:Methotrexate / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D012984:Software; D059039:Standard of Care; D055815:Young Adult
chemical_list: D000964:Antimetabolites, Antineoplastic; D002955:Leucovorin; D008727:Methotrexate