Pharmacogenomics of Tamoxifen In Female Patients: A PBPK Model-based Investigation Including The Three Main Metabolites
Kristin Dickschen (1,2), Thomas Eissing (1), Kirstin Thelen (1), Stefan Willmann (1), Georg Hempel (2), Jörg Lippert (1)
(1) Bayer Technology Services, Leverkusen, Germany; (2) Westfälische Wilhelms Universität, Münster, Germany
Objectives: This work establishes a coupled physiologically-based pharmacokinetics (PBPK) model for tamoxifen, N-desmethyltamoxifen, 4-hydroxytamoxifen and endoxifen that is able to describe their pharmacokinetics (PK) in female patients of different cytochrome P450 (CYP) 2D6 phenotypes [1].
Methods: As no human plasma concentration-time data following intravenous (i.v.) administration was available, a tamoxifen PBPK model was developed for i.v. administration of tamoxifen to rats in order to describe the disposition behavior of tamoxifen. The rat model was extrapolated accounting for human physiology. This human tamoxifen PBPK model served as a template for PBPK-models of N-desmethyltamoxifen, 4-hydroxytamoxifen and endoxifen [2]. The coupled model was used to extrapolate PK profiles for the four substances following tamoxifen single and multiple oral dose administrations to female patients with different CYP2D6 phenotypes [3,4].
Results: The rat PBPK model of tamoxifen is able to describe the disposition kinetics of tamoxifen after a single i.v. dose. Compared to experimental data, the coupled human PBPK model describes the plasma concentrations of tamoxifen, N-desmethyltamoxifen, 4-hydroxytamoxifen and endoxifen after single and multiple oral dosing of tamoxifen. The integration of known phenotype specific CYP2D6 enzyme activities into the coupled tamoxifen-endoxifen PBPK model leads to the formation of differing endoxifen plasma concentrations as reported in the literature.
Conclusions: The established PBPK model is able to describe the PK of tamoxifen and its three main metabolites in virtual female patients. Furthermore, the model can describe the influence of CYP2D6 phenotypes on plasma concentrations of endoxifen. The coupled PBPK model will be used to further investigate physiological variability in populations, especially the influence of characteristic CYP2D6 phenotype distributions in different geographical regions. Also, the model will allow the investigation of CYP2D6 inhibition and CYP3A4/5 inhibition or induction and the subsequent impact on plasma and tissue concentrations of parent drug and active metabolites. Finally, the PBPK model can be extended in order to simulate tumor response with respect to tamoxifen and endoxifen plasma and tissue concentrations influenced by CYP2D6 activity in different virtual patient populations as outlined in [5].
References:
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