A joint model for vitamin K-dependent clotting factors and anticoagulation proteins

Ooi, Q. X., Wright, D. F.B., Tait, R. C. , Isbister, G. K. and Duffull, S. B. (2017) A joint model for vitamin K-dependent clotting factors and anticoagulation proteins. Clinical Pharmacokinetics, 56(12), pp. 1555-1566. (doi: 10.1007/s40262-017-0541-5) (PMID:28409488)

Full text not currently available from Enlighten.


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.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Tait, Dr Robert
Authors: Ooi, Q. X., Wright, D. F.B., Tait, R. C., Isbister, G. K., and Duffull, S. B.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
Journal Name:Clinical Pharmacokinetics
ISSN (Online):1179-1926
Published Online:13 April 2017

University Staff: Request a correction | Enlighten Editors: Update this record