Background: Tamoxifen is widely used in the therapy for breast cancer and has three major
metabolites, N-desmethyltamoxifen, 4-hydroxytamoxifen, and endoxifen. Endoxifen has played a major
role in the inhibition of tumor growth of breast cancer and the tumor growth is related to endoxifen
Objectives: The aim of this study was to develop a pharmacokinetic-pharmacodynamic model to predict
the distribution of tamoxifen and endoxifen quantitatively, and to discover the anti-tumor effect
patterns of tamoxifen and endoxifen.
Methods: The pharmacokinetic-pharmacodynamic model was established by integrating a four compartments
pharmacokinetics model and a pharmacodynamic model, the first one include central compartment
and peripheral compartment both of which contain tamoxifen and endoxifen. The parameters
of the model were calculated by the values of plasma concentrations and the tumor growth data before
and after the administration of tamoxifen.
Results: The transport rate k42 (6.0003) of endoxifen from the peripheral compartment to the central
compartment and the metabolism rate k34 (0.0031) from tamoxifen to endoxifen in the peripheral compartment
were proven to be significant, which showed that tamoxifen and endoxifen are mainly distributed
in the central compartment. The model provided reasonable predictions of tumor growth,
which was inhibited after the administration and varies with the concentration of endoxifen.
Conclusion: We established a PK-PD model of tamoxifen and endoxifen to predict the tumor growth.
The parameters of the pharmacodynamic model, which characterized the tumor growth, revealed the
patterns of tamoxifen's anti-tumor functions. The PK-PD model successfully provided illustration for
the pharmacokinetics of tamoxifen and endoxifen, and predicted the inhibition effect of endoxifen on
the tumor growth.