Warfarin
dose individualization is typically based on a target international normalized
ratio (INR) of 2.5 with an acceptable range of 2 – 3. An INR of 2 is expected when
synthesis of the coagulation factors in the prothrombin complex has been
inhibited by 50%. Warfarin is administered as a racemic mixture of S- and R-enantiomers.
Both influence the synthesis of coagulation factors by modifying the activity of
vitamin K epoxide reductase (VKOR). S-warfarin is an inhibitor of VKOR while
R-warfarin appears to act as a competitive inhibitor of S-warfarin (Xue, Holford et
al. 2017).
The
relationship between the time course of warfarin (S- and R-) concentration and
changes in INR has been described using a turnover model for prothrombin
complex (Xue, Holford et
al. 2017). This model can be used to predict
the steady state combination of S- and R- warfarin that will achieve a target
steady state INR and the warfarin dose predicted from these target concentrations.
NextDose
uses the pharmacokinetic model for S- and R- warfarin developed to describe the
change in INR in a population of patients who had undergone cardiac surgery (Xue, Holford et
al. 2017). INR observations are used to update
Bayesian estimates of both PK and PD parameters which are then used to predict
the warfarin dose required to achieve the target iNR (Figure
1).
Figure 1 Example of INR change after started
warfarin and predicted warfarin dose to achieve a target INR of 2.
If S- or R-
warfarin concentration observations are available they can also be used to provide
information about the PK component of the warfarin model and help with dose individualization
(Figure 2).
Figure 2 Observations that may be used with
warfarin.
Both amiodarone
and fluconazole are known to inhibit metabolism of warfarin. The start and stop
dates of amiodarone and fluconazone can be entered as observations to indicate
treatment with these medications (Figure
2).
Vitamin K1
may be given to overcome the anticoagulant effect of warfarin. This effect of
vitamin K1 can be included by specifying the date that vitamin K1 is started. A
finish date one day after the start date should be entered to allow resumption
of warfarin effect (Figure
2).
Copyright All rights
reserved | Developed by Sam Holford & Nick Holford 2012-2020
Xue, L., N. Holford, X. L. Ding, Z. Y. Shen, C. R. Huang, H. Zhang, J. J. Zhang, Z. N. Guo, C. Xie, L. Zhou, Z. Y. Chen, L. S. Liu and L. Y. Miao (2017). "Theory-based pharmacokinetics and pharmacodynamics of S- and R-warfarin and effects on international normalized ratio: influence of body size, composition and genotype in cardiac surgery patients." Br J Clin Pharmacol 83(4): 823-835.