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  • 1
    Online Resource
    Online Resource
    A Novel, Enriched Population Pharmacokinetic Model for Recombinant Factor VIII-Fc Fusion Protein Concentrate in Hemophilia A Patients
    Georg Thieme Verlag KG ; 2020
    In:  Thrombosis and Haemostasis Vol. 120, No. 05 ( 2020-05), p. 747-757
    Details
    In: Thrombosis and Haemostasis, Georg Thieme Verlag KG, Vol. 120, No. 05 ( 2020-05), p. 747-757
    Abstract: Background The currently published population pharmacokinetic (PK) models used for PK-guided dosing in hemophilia patients are based on clinical trial data and usually not externally validated in clinical practice. The aim of this study was to validate a published model for recombinant factor VIII-Fc fusion protein (rFVIII-Fc) concentrate and to develop an enriched model using independently collected clinical data if required. Methods Clinical data from hemophilia A patients treated with rFVIII-Fc concentrate (Elocta) participating in the United Kingdom Extended Half-Life Outcomes Registry were collected. The predictive performance of the published model was assessed using mean percentage error (bias) and mean absolute percentage error (inaccuracy). An extended population PK model was developed using nonlinear mixed-effects modeling (NONMEM). Results A total of 43 hemophilia A patients (FVIII ≤ 2 IU/dL), aged 5 to 70 years, were included. The prior model was able to predict the collected 244 rFVIII-Fc levels without significant bias (–1.0%, 95% CI: –9.4 to 7.3%) and with acceptable accuracy (12.9%). However, clearance and central distribution volume were under predicted in patients 〈 12 years, which was expected as this age group was not represented in the previous model population. An enriched population PK model was constructed, which was able to successfully characterize PK profiles of younger children. Conclusion We concluded that the existing rFVIII-Fc population PK model is valid for patients ≥ 12 years. However, it is not reliable in younger patients. Our alternative model, constructed from real world patient data including children, allows for better description of patients ≥5 years.
    Type of Medium: Online Resource
    ISSN: 0340-6245 , 2567-689X
    URL: Article
    DOI: 10.1055/s-0040-1709522
    Language: English
    Publisher: Georg Thieme Verlag KG
    Publication Date: 2020
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  • 2
    Online Resource
    Online Resource
    Population pharmacokinetic modeling of factor concentrates in hemophilia: an overview and evaluation of best practice
    American Society of Hematology ; 2021
    In:  Blood Advances Vol. 5, No. 20 ( 2021-10-26), p. 4314-4325
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    In: Blood Advances, American Society of Hematology, Vol. 5, No. 20 ( 2021-10-26), p. 4314-4325
    Abstract: The accuracy of pharmacokinetic (PK)-guided dosing depends on the clinical and laboratory data used to construct a population PK model, as well as the patient’s individual PK profile. This review provides a detailed overview of data used for published population PK models for factor VIII (FVIII) and factor IX (FIX) concentrates, to support physicians in their choices of which model best suits each patient. Furthermore, to enhance detailed data collection and documentation, we do suggestions for best practice. A literature search was performed; publications describing prophylactic population PK models for FVIII and FIX concentrates based on original patient data and constructed using nonlinear mixed-effect modeling were included. The following data were collected: detailed demographics, type of product, assessed and included covariates, laboratory specifications, and validation of models. Included models were scored according to our recommendations for best practice, specifically scoring the quality of data documentation as reported. Respectively, 20 models for FVIII and 7 for FIX concentrates were retrieved. Although most models (22/27) included pediatric patients, only 4 reported detailed demographics. The wide range of body weights suggested that overweight and obese adults were represented. Twenty-six models reported the assay applied to measure factor levels, whereas only 16 models named reagents used. Eight models were internally validated using a data subset. This overview presents detailed information on clinical and laboratory data used for published population PK models. We provide recommendations on data collection and documentation to increase the reliability of PK-guided prophylactic dosing of factor concentrates in hemophilia A and B.
    Type of Medium: Online Resource
    ISSN: 2473-9529 , 2473-9537
    URL: Article
    DOI: 10.1182/bloodadvances.2021005096
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
    detail.hit.zdb_id: 2876449-3
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  • 3
    Online Resource
    Online Resource
    Marfan syndrome in adolescence: adolescents’ perspectives on (physical) functioning, disability, contextual factors and support needs
    Springer Science and Business Media LLC ; 2019
    In:  European Journal of Pediatrics Vol. 178, No. 12 ( 2019-12), p. 1883-1892
    Details
    In: European Journal of Pediatrics, Springer Science and Business Media LLC, Vol. 178, No. 12 ( 2019-12), p. 1883-1892
    Abstract: Although essential for providing optimal adolescent patient support, knowledge of the impact of Marfan syndrome in adolescence is limited. To explore adolescents’ perceived impact of Marfan syndrome on (physical) functioning (activities, participation), disability (limitations, restrictions), contextual factors and support needs, we interviewed 19 adolescents with Marfan syndrome. Audio-recordings were transcribed, coded and analysed using thematic analysis. Identified themes were “difficulties in keeping up with peers” and “being and feeling different from peers”. Furthermore, an adolescent Marfan syndrome-specific International Classification of Functioning, Disability and Health for Children and Youth (ICF-CY) model derived from the data describing the adolescent perceived impact of Marfan syndrome on functioning, disability and its contextual factors. Adolescents perceived problems in keeping up with peers in school, sports, leisure and friendships/relationships, and they could not meet work requirements. Moreover, participants perceived to differ from peers due to their appearance and disability. Contextual factors: coping with Marfan syndrome, self-esteem/image, knowledge about Marfan syndrome, support from family/friends/teachers, ability to express needs and peer-group acceptation acted individually as barrier or facilitator for identified themes. Conclusion : Adolescents with Marfan syndrome perceived limitations and restrictions in (physical) functioning. They perceived problems in keeping up with peers and perceived to differ from peers due to their appearance and disability. This warrants awareness and tailored physical, psychosocial, educational and environmental support programmes to improve (physical) functioning and empowerment of adolescents with Marfan syndrome. What is known: • Marfan syndrome is a hereditary connective tissue disorder. • Marfan syndrome affects multiple systems. What is new: • Adolescents with Marfan syndrome perceive (1) problems in keeping up with peers in school, sports, leisure, friendships/relationships and work (2) to differ from peers due to their appearance and disability. • An adolescent Marfan syndrome-specific International Classification of Functioning, Disability and Health for Children and Youth model derived from the data describing the adolescent perceived impact of Marfan syndrome on functioning, disability and contextual factors.
    Type of Medium: Online Resource
    ISSN: 0340-6199 , 1432-1076
    URL: Article
    DOI: 10.1007/s00431-019-03469-7
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2019
    detail.hit.zdb_id: 2647723-3
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