Individualized factor IX dosing in two brothers: application of longitudinal pharmacokinetic modelling to optimize therapeutic benefit

Brown, Jacob T.; Wicklund, Brian M.; Abdel‐Rahman, Susan M.

doi:10.1111/hae.12593

Cited by 2 publications

(1 citation statement)

References 7 publications

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“…1 In fact, PK strategies have been used to guide the replacement of various clotting factors for more than two decades. [2][3][4][5] Successful application of PK-guided dose individualization to routine patient care requires (1) comprehensive knowledge of the patient, (2) a thorough understanding of the pharmacologic principles that drive the relationship between doseexposure, and (3) expertise in mathematical and PK modeling and simulation. 6 Providers with expert knowledge of the latter often have limited involvement with the patient or their primary medical team and engaging them outside the normal flow of care can introduce delays in arriving at the best dosing solution for the patient.…”

Section: Background and Significancementioning

confidence: 99%

Design and Usability of an Electronic Health Record—Integrated, Point-of-Care, Clinical Decision Support Tool for Modeling and Simulation of Antihemophilic Factors

et al. 2020

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Background With the consequences of inadequate dosing ranging from increased bleeding risk to excessive drug costs and undesirable administration regimens, the antihemophilic factors are uniquely suited to dose individualization. However, existing options for individualization are limited and exist outside the flow of care. We developed clinical decision support (CDS) software that is integrated with our electronic health record (EHR) and designed to streamline the process for our hematology providers. Objectives The aim of this study is to develop and examine the usability of a CDS tool for antihemophilic factor dose individualization. Methods Our development strategy was based on the features associated with successful CDS tools and driven by a formal requirements analysis. The back-end code was based on algorithms developed for manual individualization and unit tested with 23,000 simulated patient profiles created from the range of patient-derived pharmacokinetic parameter estimates defined in children and adults. A 296-item heuristic checklist was used to guide design of the front-end user interface. Content experts and end-users were recruited to participate in traditional usability testing under an institutional review board approved protocol. Results CDS software was developed to systematically walk the point-of-care clinician through dose individualization after seamlessly importing the requisite patient data from the EHR. Classical and population pharmacokinetic approaches were incorporated with clearly displayed estimates of reliability and uncertainty. Users can perform simulations for prophylaxis and acute bleeds by providing two of four therapeutic targets. Testers were highly satisfied with our CDS and quickly became proficient with the tool. Conclusion With early and broad stakeholder engagement, we developed a CDS tool for hematology provider that affords seamless transition from patient assessment, to pharmacokinetic modeling and simulation, and subsequent dose selection.

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Section: Background and Significancementioning

confidence: 99%

Design and Usability of an Electronic Health Record—Integrated, Point-of-Care, Clinical Decision Support Tool for Modeling and Simulation of Antihemophilic Factors

et al. 2020

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Strategies for Individualized Dosing of Clotting Factor Concentrates and Desmopressin in Hemophilia A and B

Preijers

Schütte

Kruip

et al. 2019

Therapeutic Drug Monitoring

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Hemophilia A and hemophilia B are hereditary bleeding disorders, caused by a deficiency of clotting factor VIII or clotting factor IX, respectively. To treat and prevent bleedings, patients can administer clotting factor concentrates (hemophilia A and B) or desmopressin (hemophilia A). Both clotting factor concentrates and desmopressin are currently dosed according to the patients' body weight. However, clotting factor concentrates exhibit considerable pharmacokinetic (PK) variability. Therefore, several alternative dosing strategies to individualize dosing of clotting factor concentrates and desmopressin in hemophilia A and B have been proposed. In this study, a review of the existing literature on the individualization of dosing based on PK guidance was performed. In total, 79 articles were included. The methods to individualize dosing were divided into 3 categories: (1) methods using clinical parameters, (2) empirical individual PK-guided methods, and (3) maximum a posteriori (MAP) Bayesian estimation methods. The clinical parameter mainly used to individualize dosing is bleeding phenotype. Dosing based on bleeding phenotype may decrease clotting factor consumption. However, with this method, it is not possible to individualize on-demand dosing during bleeding events or in the perioperative setting. Empirical individual PK-guided methods can be used both for prevention and treatment of bleedings. These methods include dose individualization using a nomogram and individualized in vivo recovery. In the perioperative setting, adjustment of the rate of continuous infusion can be applied to obtain a specific target level. The final category, MAP Bayesian estimation methods, relies on the availability of a population PK model. In total, 22 population PK models describing clotting factor concentrate or desmopressin dosing are currently available in literature. MAP Bayesian estimates can be used to calculate the individualized doses required to achieve or maintain a target level in every setting. The application of PK-guided and pharmacodynamic-guided dosing of clotting factor concentrates and desmopressin seems promising, although further investigation is warranted. Prospective studies analyzing its potential benefit are on the way.

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Individualized factor IX dosing in two brothers: application of longitudinal pharmacokinetic modelling to optimize therapeutic benefit

Cited by 2 publications

References 7 publications

Design and Usability of an Electronic Health Record—Integrated, Point-of-Care, Clinical Decision Support Tool for Modeling and Simulation of Antihemophilic Factors

Design and Usability of an Electronic Health Record—Integrated, Point-of-Care, Clinical Decision Support Tool for Modeling and Simulation of Antihemophilic Factors

Strategies for Individualized Dosing of Clotting Factor Concentrates and Desmopressin in Hemophilia A and B

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