Electronic Health Record–Embedded Decision Support Platform for Morphine Precision Dosing in Neonates

Vinks, Alexander A.; Punt, Nieko; Menke, Frank; Kirkendall, Eric S.; Butler, Dawn; Duggan, Thomas J.; Cortezzo, DonnaMaria E.; Kiger, Sam; Dietrich, Tom; Spencer, Paul; Keefer, Rob; Setchell, Kenneth D.R.; Zhao, Junfang; Euteneuer, Joshua C.; Mizuno, Tomoyuki; Dufendach, Kevin

doi:10.1002/cpt.1684

Cited by 34 publications

(46 citation statements)

References 35 publications

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“…A module for Bayesian estimation was included in the MTXPK.org platform using a three-compartment structure model developed using the visual PK/pharmacodynamic (PD) model designer Edsim++ (Mediware, Prague, Czech Republic) and executed using an Edsim++ compatible PK/PD modeling engine. 26,27 Evaluation of MTX population PK models Two published MTX population PK models. 18,28 and our three-compartment MTX model were tested in an MTXPK.org prototype (MTXSim), which uses the same platform libraries as MTXPK.org.…”

Section: Model Development and Bayesian Estimationmentioning

confidence: 99%

“…This MTX-specific library uses a general purpose PK/PD modeling engine for simulation and Bayesian estimation, which, in turn, uses models from a PK/PD model repository. 27 MTX models were designed, executed, and validated using Edsim++ 1.80 (Mediware). 26 The PK/PD modeling engine runtime is capable of executing these models outside Edsim++.…”

Section: Model Development and Bayesian Estimationmentioning

confidence: 99%

“…Model parameters for each of the published population PK models are summarized in Table S1. The model parameters were integrated into the MTXSim prototype with Edsim++ PK engine functionality, 26,27 which enabled us to load patient data from a previously published cohort 29 onto each model to generate individual Bayesian estimated PK estimations. Comparisons between PK estimates and observed values were made.…”

Section: Evaluation Of Mtx Population Pk Modelsmentioning

confidence: 99%

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MTXPK.org: A Clinical Decision Support Tool Evaluating High‐Dose Methotrexate Pharmacokinetics to Inform Post‐Infusion Care and Use of Glucarpidase

Taylor

Mizuno

Punt³

et al. 2020

Clin Pharma and Therapeutics

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Methotrexate (MTX), an antifolate, 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 SDs 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 laboratory 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 3‐compartment MTX population pharmacokinetic (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.

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Section: Model Development and Bayesian Estimationmentioning

confidence: 99%

Section: Model Development and Bayesian Estimationmentioning

confidence: 99%

Section: Evaluation Of Mtx Population Pk Modelsmentioning

confidence: 99%

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MTXPK.org: A Clinical Decision Support Tool Evaluating High‐Dose Methotrexate Pharmacokinetics to Inform Post‐Infusion Care and Use of Glucarpidase

Taylor

Mizuno

Punt³

et al. 2020

Clin Pharma and Therapeutics

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“…Real-time monitoring with integrated data may also be used for other drugs. Vinks et al recently provided a real-time bedside decision support system with drug exposure and response for morphine administration in neonatal pain management (Vinks et al, 2019). The safety of morphine could be monitored using continuous physiological data (Hartley et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Precision Dosing of Doxapram in Preterm Infants Using Continuous Pharmacodynamic Data and Model-Based Pharmacokinetics: An Illustrative Case Series

et al. 2020

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Conclusion: Real-time and non-invasive effect monitoring of drug therapy combined with model-based exposure provides relevant information to clinicians and can importantly improve therapy. The variability between and within patients emphasizes the importance of individual, objective evaluation of pharmacotherapy. These measurements, together with data on ADRs, allow for precision medicine in neonatology that should be brought to the bedside.

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“…At Cincinnati Children's Hospital Medical Center, we developed an electronic health record-linked decision support platform for precision dosing of morphine in neonates. 62 This population PK/PD model-informed precision dosing platform using Bayesian estimation allows the clinician to adjust the dosing regimen to optimize the drug therapy in real time. The example in Figure 3 shows the predicted morphine PK profile (blue line on the left panel and dashed red line in the right panel) based on the infant's weight and gestational age and dosing regimen administered (continuous infusion plus bolus doses as needed, based on the pain scores).…”

Section: Clinical Example: Using Bayesian Methods To Optimize Morphinmentioning

confidence: 99%

Suggestions for Model‐Informed Precision Dosing to Optimize Neonatal Drug Therapy

Euteneuer

Kamatkar

Fukuda

et al. 2018

The Journal of Clinical Pharma

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Evidence for dosing, efficacy, and safety of most medications used to treat neonates is sparse. Thus, dosing is usually derived by extrapolation from adult and pediatric pharmacologic data with scaling by body weight or body surface area. This may lead to drug dosing that is unsafe or ineffective. However, new strategies are being developed and studied to dose medications in critically ill neonates. Mass spectroscopy technology capable of quickly analyzing drug levels is readily available. Software that integrates population pharmacokinetics and pharmacodynamics with data from sparse samples from neonates allows for timely adjustments of dosing to achieve the desired effect while minimizing adverse outcomes. Some genetic polymorphisms that affect drug response in neonates have also been reported. This review highlights aspects of drug response and how it is impacted by prematurity, assesses pharmacogenomic studies in neonates, and offers suggestions for innovative pharmacokinetic/pharmacodynamic model-based approaches that combine population- or physiology-based pharmacology data, Bayesian analysis, and electronic decision support tools for precision dosing in neonates while illustrating examples where this approach can be used to optimize medical therapy in neonates. Barriers to implementing precision dosing in neonates and how to overcome them are also discussed.

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Electronic Health Record–Embedded Decision Support Platform for Morphine Precision Dosing in Neonates

Abstract: Morphine is the opioid most commonly used for neonatal pain management. In intravenous form, it is administered as continuous infusions and intermittent injections, mostly based on empirically

Cited by 34 publications

References 35 publications

MTXPK.org: A Clinical Decision Support Tool Evaluating High‐Dose Methotrexate Pharmacokinetics to Inform Post‐Infusion Care and Use of Glucarpidase

MTXPK.org: A Clinical Decision Support Tool Evaluating High‐Dose Methotrexate Pharmacokinetics to Inform Post‐Infusion Care and Use of Glucarpidase

Precision Dosing of Doxapram in Preterm Infants Using Continuous Pharmacodynamic Data and Model-Based Pharmacokinetics: An Illustrative Case Series

Suggestions for Model‐Informed Precision Dosing to Optimize Neonatal Drug Therapy

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