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Rotational thromboelastometry can predict the probability of bleeding events in a translational rat model of haemophilia A following gene-based FVIIa prophylaxis.

Authors
  • Larsen, Malte Selch1, 2
  • Vestergaard Juul, Rasmus3
  • Zintner, Shannon M4
  • T Kristensen, Annemarie2
  • Margaritis, Paris4, 5, 6
  • Kjelgaard-Hansen, Mads1
  • Wiinberg, Bo1
  • Simonsson, Ulrika S H7
  • Kreilgaard, Mads1
  • 1 Haemophilia Research, Global Research, Novo Nordisk A/S, Maaloev, Denmark. , (Denmark)
  • 2 Department of Veterinary Clinical Sciences, University of Copenhagen, Frederiksberg, Denmark. , (Denmark)
  • 3 Quantitative Clinical Pharmacology, Novo Nordisk A/S, Soeborg, Denmark. , (Denmark)
  • 4 Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • 5 The Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • 6 The University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.
  • 7 Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden. , (Sweden)
Type
Published Article
Journal
Haemophilia : the official journal of the World Federation of Hemophilia
Publication Date
Dec 04, 2019
Identifiers
DOI: 10.1111/hae.13899
PMID: 31797491
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Monitoring of clinical effectiveness of bypassing agents in haemophilia patients is hampered by the lack of validated laboratory assays. Thromboelastography (TEG) and rotational thromboelastometry (ROTEM) have been evaluated for predicting clinical effectiveness of bypassing agents, however, with limited success. Application of a longitudinal model-based approach may allow for a quantitative characterization of the link between ROTEM parameters and the probability of bleeding events. We analyse longitudinal data from haemophilia A rats receiving gene-based FVIIa prophylaxis in terms of total circulatory levels of FVII/FVIIa, clotting time (CT) measured using ROTEM and the probability of bleeding events. Using population pharmacokinetic-pharmacodynamic (PKPD) modelling, a PK-CT-repeated time-to-event (RTTE) model was developed composed of three submodels (a) a FVII/FVIIa PK model, (b) a PK-CT model describing the relationship between predicted FVIIa expression and CT and (c) a RTTE model describing the probability of bleeding events as a function of CT. The developed PK-CT-RTTE model accurately described the vector dose-dependent plasma concentration-time profile of total FVII/FVIIa and the exposure-response relationship between AAV-derived FVIIa expression and CT. Importantly, the developed model accurately described the occurrence of bleeding events over time in a quantitative manner, revealing a linear relationship between predicted change from baseline CT and the probability of bleeding events. Using PK-CT-RTTE modelling, we demonstrated that ROTEM parameters can accurately predict the probability of bleeding events in a translational animal model of haemophilia A. © 2019 John Wiley & Sons Ltd.

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