nlmixr

Warfarin

Models for warfarin PKPD involve a PK model, a PD model and a link model to describe the delay between changes in PK model predicted concentration and the resultng effect. Warfarin effect is described by the change in Prothrombin Complex Activity PCA which is inversely proportional to the usual clinical measurement of the International Normalized Ratio (INR).

nlmixr was used to estimate the parameters of a PK, PD and link model (immediate, effect compartment or turnover) using a simulated data set (ka1_to_emax_simtr2_10.csv) describing total racemic warfarin plasma concentrations and PCA in 32 subjects. The simulated data is based on an original warfarin data (warfarin_dat.csv) obtained from publications by O'Reilly et al. (1963,1968). The estimation script Warfarin PKPD simtr2.Rmd is provided as an R markdown file. The results for the simulated data are shown in Warfarin PKPD simtr2.html. Changing the datadir path allows other users to use the script with the supplied data sets. Changing the issim parameter in the Rmd file from 3 to 0) allows this script to use the original data.


O'Reilly RA, Aggeler PM, Leong LS. Studies of the coumarin anticoagulant drugs: The pharmacodynamics of warfarin in man. J Clin Invest. 1963;42(10):1542-51.
O'Reilly RA, Aggeler PM. Studies on coumarin anticoagulant drugs. Initiation of warfarin therapy without a loading dose. Circulation. 1968;38:169-77