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A Joint Model for Vitamin K-Dependent Clotting Factors and Anticoagulation Proteins

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Abstract

Background

Warfarin acts by inhibiting the reduction of vitamin K (VK) to its active form, thereby decreasing the production of VK-dependent coagulation proteins. The aim of this research is to develop a joint model for the VK-dependent clotting factors II, VII, IX and X, and the anticoagulation proteins, proteins C and S, during warfarin initiation.

Methods

Data from 18 patients with atrial fibrillation who had warfarin therapy initiated were available for analysis. Nine blood samples were collected from each subject at baseline, and at 1–5, 8, 15 and 29 days after warfarin initiation and assayed for factors II, VII, IX and X, and proteins C and S. Warfarin concentration–time data were not available. The coagulation proteins data were modelled in a stepwise manner using NONMEM® Version 7.2. In the first stage, each of the coagulation proteins was modelled independently using a kinetic-pharmacodynamic model. In the subsequent step, the six kinetic-pharmacodynamic models were combined into a single joint model.

Results

One patient was administered VK and was excluded from the analysis. Each kinetic-pharmacodynamic model consisted of two parts: (1) a common one-compartment pharmacokinetic model with first-order absorption and elimination for warfarin; and (2) an inhibitory E max model linked to a turnover model for coagulation proteins. In the joint model, an unexpected pharmacodynamic lag was identified and the estimated degradation half-life of VK-dependent coagulation proteins were in agreement with previously published values. The model provided an adequate fit to the observed data.

Conclusion

The joint model represents the first work to quantify the influence of warfarin on all six VK-dependent coagulation proteins simultaneously. Future work will expand the model to predict the influence of exogenously administered VK on the time course of clotting factor concentrations after warfarin overdose and during perioperative warfarin reversal procedures.

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Acknowledgements

Dr. David Foster, University of South Australia and Dr. Stefanie Hennig, University of Queensland offered their multicore facilities for parallel computing and helped execute some of the NONMEM® runs.

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Authors and Affiliations

  1. School of Pharmacy, University of Otago, PO Box 56, Dunedin, 9054, New Zealand

    Qing Xi Ooi, Daniel F. B. Wright & Stephen B. Duffull

  2. Glasgow Royal Infirmary, Glasgow, Scotland, UK

    R. Campbell Tait

  3. School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia

    Geoffrey K. Isbister

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  1. Qing Xi Ooi
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  2. Daniel F. B. Wright
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Correspondence to Qing Xi Ooi.

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Conflict of Interest

Qing Xi Ooi, Daniel F.B. Wright, R. Campbell Tait, Geoffrey K. Isbister and Stephen B. Duffull have no conflicts of interest that are directly relevant to the contents of this study.

Consent to Participate

Informed consent was obtained from all individual participants included in the study. Additional informed consent was obtained from all individual participants for whom identifying information is included in this article.

Ethics approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Funding

Qing Xi Ooi received the University of Otago doctoral scholarship. Geoffrey K. Isbister is funded by a National Health and Medical Research Council Senior Research Fellowship, ID 1061041. No funding was received for this study.

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Ooi, Q.X., Wright, D.F.B., Tait, R.C. et al. A Joint Model for Vitamin K-Dependent Clotting Factors and Anticoagulation Proteins. Clin Pharmacokinet 56, 1555–1566 (2017). https://doi.org/10.1007/s40262-017-0541-5

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