Dosing for Personalized Prophylaxis in Hemophilia A Highly Varies on the Underlying Population Pharmacokinetic Models.
Journal
Therapeutic drug monitoring
ISSN: 1536-3694
Titre abrégé: Ther Drug Monit
Pays: United States
ID NLM: 7909660
Informations de publication
Date de publication:
01 10 2022
01 10 2022
Historique:
received:
22
12
2021
accepted:
21
02
2022
pubmed:
1
4
2022
medline:
16
9
2022
entrez:
31
3
2022
Statut:
ppublish
Résumé
Model-informed personalized prophylaxis with factor VIII (FVIII) replacement therapy aimed at higher trough levels is becoming indispensable for patients with severe hemophilia A. This study aimed to identify the most suitable population pharmacokinetic (PK) models for personalized prophylaxis using various FVIII products and 2 clinical assays and to implement the most suitable one in open-access software. Twelve published population PK models were systematically compared to predict the time above target (TaT) for a reference dosing occasion. External validation was performed using a 5-point PK data from 39 adult patients with hemophilia A with FVIII measured by chromogenic substrate (CSA) and 1-stage assays (OSAs) using NONMEM under 3 different conditions: a priori (with all FVIII samples blinded), a posteriori (with 1 trough sample), and general model fit (with all FVIII samples including the reference dosing occasion provided). On average, the baseline covariate models overpredicted TaT (a priori; bias -3.8 hours to 49.6 hours). When additionally including 1 previous trough FVIII sample before the reference dosing occasion (a posteriori), only 50% of the models improved in bias (-1.0 hours to 36.5 hours) and imprecision (22.4 hours and 60.7 hours). Using all the time points (general model fit), the models accurately predicted (individual TaT less than ±12 hours compared with the reference) 62%-90% and 33%-74% of the patients using CSA and OSA data, respectively. Across all scenarios, predictions using CSA data were more accurate than those using the OSA data. One model performed best across the population (bias: -3.8 hours a priori, -1.0 hours a posteriori , and 0.6 hours general model fit ) and acceptably predicted 44% (a priori) to 90% ( general model fit ) of the patients. To allow the community-based evaluation of patient-individual FVIII dosing, this model was implemented in the open-access model-informed precision dosing software "TDMx."
Sections du résumé
BACKGROUND
Model-informed personalized prophylaxis with factor VIII (FVIII) replacement therapy aimed at higher trough levels is becoming indispensable for patients with severe hemophilia A. This study aimed to identify the most suitable population pharmacokinetic (PK) models for personalized prophylaxis using various FVIII products and 2 clinical assays and to implement the most suitable one in open-access software.
METHODS
Twelve published population PK models were systematically compared to predict the time above target (TaT) for a reference dosing occasion. External validation was performed using a 5-point PK data from 39 adult patients with hemophilia A with FVIII measured by chromogenic substrate (CSA) and 1-stage assays (OSAs) using NONMEM under 3 different conditions: a priori (with all FVIII samples blinded), a posteriori (with 1 trough sample), and general model fit (with all FVIII samples including the reference dosing occasion provided).
RESULTS
On average, the baseline covariate models overpredicted TaT (a priori; bias -3.8 hours to 49.6 hours). When additionally including 1 previous trough FVIII sample before the reference dosing occasion (a posteriori), only 50% of the models improved in bias (-1.0 hours to 36.5 hours) and imprecision (22.4 hours and 60.7 hours). Using all the time points (general model fit), the models accurately predicted (individual TaT less than ±12 hours compared with the reference) 62%-90% and 33%-74% of the patients using CSA and OSA data, respectively. Across all scenarios, predictions using CSA data were more accurate than those using the OSA data.
CONCLUSIONS
One model performed best across the population (bias: -3.8 hours a priori, -1.0 hours a posteriori , and 0.6 hours general model fit ) and acceptably predicted 44% (a priori) to 90% ( general model fit ) of the patients. To allow the community-based evaluation of patient-individual FVIII dosing, this model was implemented in the open-access model-informed precision dosing software "TDMx."
Identifiants
pubmed: 35358115
doi: 10.1097/FTD.0000000000000983
pii: 00007691-202210000-00009
doi:
Substances chimiques
Factor VIII
9001-27-8
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
665-673Informations de copyright
Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.
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