Use of population PK/PD approach to model the thrombin generation assay: assessment in haemophilia A plasma samples spiked by a TFPI antibody.
Coagulation
Empirical model
Non-linear mixed-effects modelling
PK/PD model
Thrombin generation assay
Journal
Journal of pharmacokinetics and pharmacodynamics
ISSN: 1573-8744
Titre abrégé: J Pharmacokinet Pharmacodyn
Pays: United States
ID NLM: 101096520
Informations de publication
Date de publication:
Aug 2021
Aug 2021
Historique:
received:
25
09
2020
accepted:
22
03
2021
pubmed:
14
4
2021
medline:
29
1
2022
entrez:
13
4
2021
Statut:
ppublish
Résumé
The thrombin generation (TG) assay is a well-established tool to capture the clotting potential of any healthy or haemophiliac subject. It measures ex vivo the kinetics of thrombin activation throughout the coagulation. Clinical studies allowed to create two databases gathering the coagulation factor levels and the thrombin generation profile of 40 healthy and 40 haemophiliac A (HA) subjects. Besides, portions of all HA samples were spiked with increasing levels of a TFPI antibody (considered as a possible therapeutic target) and corresponding TG profiles were determined. The non-linear mixed-effect (NLME) modelling aims at describing and explaining the experimentally observed important variability of the TG curves between subjects and the individual effects of spiking with a TFPI antibody. The models consist of an empirical description of the TG kinetics, accounting for an additive residual error and between-subject variability on its parameters. Factor VIII and TFPI were found to significantly explain and reduce the variability of the TG of haemophilia A samples. Besides, the model is shown to correctly reproduce the variability in the response to the ex vivo spiking with the TFPI antibody, by combining the empirical description of TG to a simple Hill equation that accounts for the binding between TFPI and different doses of its antibody. Such models can be useful for clinical practice, with the analysis and comparison of the distributions of TG profiles in healthy and haemophilia populations; and also for research, with the analysis of the effect of TFPI and its neutralization on individual TG profiles.
Identifiants
pubmed: 33846873
doi: 10.1007/s10928-021-09752-1
pii: 10.1007/s10928-021-09752-1
doi:
Substances chimiques
Antibodies
0
Lipoproteins
0
lipoprotein-associated coagulation inhibitor
0
Thrombin
EC 3.4.21.5
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
563-580Références
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