A Novel, Enriched Population Pharmacokinetic Model for Recombinant Factor VIII-Fc Fusion Protein Concentrate in Hemophilia A Patients

Bukkems, Laura H.; Heijdra, Jessica M.; Mathias, Mary; Collins, Peter William; Hay, C. R. M.; Tait, R. C.; Mangles, Sarah; Myers, Bethan; Evans, Gillian; Bailiff, Benjamin; Curry, Nicola; Payne, Jeanette; Austin, Steve; Goedhart, Tine M. H. J.; Leebeek, Frank W.G.; Meijer, Karina; Fijnvandraat, Karin; Chowdary, Pratima; Mathôt, Ron A. A.; Cnossen, Marjon H.

doi:10.1055/s-0040-1709522

Cited by 12 publications

(20 citation statements)

References 28 publications

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“…Population PK models of the concentrates published in the literature were used by the Monte Carlo method to simulate the FVIII level versus time profiles. 12,[17][18][19][20][21] The PK parameters and equations used in the population PK models are presented in ►Supplementary Tables S1 to S4 (available in the online version).…”

Section: Monte Carlo Simulationsmentioning

confidence: 99%

“…[14][15][16] Fortunately, population PK models of the various FVIII concentrates have been published or are publicly available that describe the PK of the FVIII concentrates in a typical patient as well as the intraand interindividual variability. [17][18][19][20][21] With these population PK models, Monte Carlo simulations can be performed. In this manner, individual PK profiles of a virtual population are obtained that match the patient characteristics of the population from which the model was constructed, while no costs are made and patients are not exposed to therapeutic interventions.…”

Section: Introductionmentioning

confidence: 99%

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Comparison of the Pharmacokinetic Properties of Extended Half-Life and Recombinant Factor VIII Concentrates by In Silico Simulations

Bukkems¹,

Preijers²,

Spengler³

et al. 2021

Thromb Haemost

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Background The pharmacokinetic (PK) properties of extended half-life (EHL) factor VIII (FVIII) concentrates differ, leading to variation in the optimal dosing regimen for the individual patient. The aim of this study was to establish these PK differences for various EHL FVIII concentrates by in silico simulations. Methods FVIII level over time profiles of rFVIII-SC, BAY 81–8973, rFVIII-Fc, BAX 855, BAY 94–9027, and standard half-life (SHL) rFVIII concentrates were simulated for 1,000 severe hemophilia A patients during steady-state dosing of 40 IU/kg every 72 hours or dosing as advised in the summary of product characteristics (SmPC). Results Although the elimination half-life values were comparable for rFVIII-FC, BAX 855, and BAY 94–9027, a higher area under the curve (AUC; 2,779 IU/h/dL) for BAY 94–9027 was obtained. During steady-state dosing of 40 IU/kg every 72 hours, 58.5% (rFVIII-SC), 69.3% (BAY 81–8972), 89.0% (rFVIII-Fc), 83.9% (BAX 855), and 93.7% (BAY 94–9027) of the patients maintained a trough level of 1 IU/dL, compared with 56.0% for SHL rFVIII. Following dosing schemes described in the SmPC, between 51.0 and 65.4% or 23.2 and 31.1% of the patients maintained a target trough level of 1 IU/dL or 3 IU/dL, respectively. Conclusion BAY 94–9027 showed the largest increase of AUC and best target attainment compared with SHL rFVIII, followed closely by BAX 855 and rFVIII-Fc. BAY 81–8973 and rFVIII-SC showed smaller PK improvements. Although our analyses increase insight into the PK of these FVIII concentrates, more studies evaluating the relation between factor levels and bleeding risk are needed.

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Section: Monte Carlo Simulationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Comparison of the Pharmacokinetic Properties of Extended Half-Life and Recombinant Factor VIII Concentrates by In Silico Simulations

Bukkems¹,

Preijers²,

Spengler³

et al. 2021

Thromb Haemost

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“…This resulted in an increase of FVIII levels from 100 IU/dL when measured by OSA compared with 131 IU/dL when measured by CSA. 24 Because reagents have been identified as the most important cause of assay variability, 16 it is striking that we were not able to identify the used reagent of 11/27 models. Interestingly, we identified 16 different documented reagents.…”

Section: Laboratory Datamentioning

confidence: 97%

“…19 In Bukkems et al, it was shown that population clearance and central volume of distribution were underpredicted in patients aged ,12 years when applying a population PK model based solely on patients 12 years and older. 24 Overweight and obese adults are represented in most models. This is clinically relevant because of the increasing prevalence of overweight/ obesity in 31% of hemophilia patients in Europe and North American, with concomitant risks of under-or overdosing of factor concentrates.…”

Section: Patient Characteristicsmentioning

confidence: 99%

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Population pharmacokinetic modeling of factor concentrates in hemophilia: an overview and evaluation of best practice

et al. 2021

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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 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 non-linear 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, twenty models for FVIII and seven for FIX concentrates were retrieved. Although most models (22/27) included pediatric patients, only four 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.

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A Generative and Causal Pharmacokinetic Model for Factor VIII in Hemophilia A: A Machine Learning Framework for Continuous Model Refinement

Janssen,

Smalbil,

Bennis

et al. 2024

Clin Pharma and Therapeutics

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In rare diseases, such as hemophilia A, the development of accurate population pharmacokinetic (PK) models is often hindered by the limited availability of data. Most PK models are specific to a single recombinant factor VIII (rFVIII) concentrate or measurement assay, and are generally unsuited for answering counterfactual (“what‐if”) queries. Ideally, data from multiple hemophilia treatment centers are combined but this is generally difficult as patient data are kept private. In this work, we utilize causal inference techniques to produce a hybrid machine learning (ML) PK model that corrects for differences between rFVIII concentrates and measurement assays. Next, we augment this model with a generative model that can simulate realistic virtual patients as well as impute missing data. This model can be shared instead of actual patient data, resolving privacy issues. The hybrid ML‐PK model was trained on chromogenic assay data of lonoctocog alfa and predictive performance was then evaluated on an external data set of patients who received octocog alfa with FVIII levels measured using the one‐stage assay. The model presented higher accuracy compared with three previous PK models developed on data similar to the external data set (root mean squared error = 14.6 IU/dL vs. mean of 17.7 IU/dL). Finally, we show that the generative model can be used to accurately impute missing data (< 18% error). In conclusion, the proposed approach introduces interesting new possibilities for model development. In the context of rare disease, the introduction of generative models facilitates sharing of synthetic data, enabling the iterative improvement of population PK models.

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A Novel, Enriched Population Pharmacokinetic Model for Recombinant Factor VIII-Fc Fusion Protein Concentrate in Hemophilia A Patients

Cited by 12 publications

References 28 publications

Comparison of the Pharmacokinetic Properties of Extended Half-Life and Recombinant Factor VIII Concentrates by In Silico Simulations

Comparison of the Pharmacokinetic Properties of Extended Half-Life and Recombinant Factor VIII Concentrates by In Silico Simulations

Population pharmacokinetic modeling of factor concentrates in hemophilia: an overview and evaluation of best practice

A Generative and Causal Pharmacokinetic Model for Factor VIII in Hemophilia A: A Machine Learning Framework for Continuous Model Refinement

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