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A coupled PBPK-model of tamoxifen and its three main metabolites

By Susan Hunt,2014-03-18 09:53
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    Title: A coupled PBPK-model of tamoxifen and its three main metabolites to investigate the influence of CYP2D6 polymorphism on endoxifen formation

    Authors: Kristin Dickschen (1,2), Thomas Eissing (1), Stefan Willmann (1), Georg Hempel (2), Jörg Lippert (1)*

    Institutions: (1) Bayer Technology Services, Leverkusen, Germany; (2) Westfälische Wilhelms-University, Münster, Germany

Objectives:

    Tamoxifen is a first-line endocrine agent in the adjuvant treatment of estrogen receptor positive mammary carcinoma and administered to breast cancer patients all over the world. Endoxifen, a secondary metabolite of tamoxifen, is considered to be important for its anti-tumoral activity as it exerts higher affinity and inhibition potency for estrogen receptor alpha compared to the parent drug [1,2,3].

    In humans, endoxifen is formed via two routes distinguished by the sequence of N-demethylation predominantly mediated by cytochrome P450 3A4/5 (CYP3A4/5) and 4-hydroxylation mainly mediated by the polymorphic CYP2D6. The first, major route proceeds via N-desmethyltamoxifen, while the second, minor route proceeds via 4-hydroxtamoxifen, whereby the latter is generally present in minor concentrations. The involvement of the polymorphic CYP2D6 in both routes probably leads to a high inter-individual variability in endoxifen formation among patients with different phenotypes and may eventually cause clinically relevant influences on therapy outcome [1,2,3]. However, recent studies have reported contradicting results concerning the question whether or not impaired CYP2D6 enzyme activity may significantly affect the treatment benefit of tamoxifen [3,4].

    The aim of this work was to establish a coupled PBPK-model of the four substances, namely tamoxifen, N-desmethyltamoxifen, 4-hydroxytamoxifen and endoxifen that is able to describe the PK in female patients of different CYP2D6 phenotypes based on reported differences in the enzyme activity.

Methods:

    A tamoxifen PBPK model was developed for the intravenous administration of tamoxifen in rats and compared to published plasma-concentration-time PK data in order to describe the disposition behavior of tamoxifen adequately, as no human iv-data were available.

    The rat model was then scaled to account for human physiology. The human tamoxifen PBPK model also served as a template for PBPK-models of N-desmethyltamoxifen, 4-hydroxytamoxifen and endoxifen for which altered physicochemical properties were taken into account. The coupled model of the four substances was used to extrapolate PK profiles for the four substances following tamoxifen single and multiple dose administration schemes in different CYP2D6 phenotypes. The results were compared to different data reported in literature including endoxifen steady-state concentrations in phenotyped female breast cancer patients.

Results:

    The PBPK model of tamoxifen is able to describe the disposition kinetics of tamoxifen after a single intravenous administration in rats. The rat model was also used to simulate oral administration schemes and a comparison to reported data supports the idea of solubility-limited absorption for the given dose in rats.

    Based on a comparison to experimental data, the coupled human PBPK model is able to describe the plasma concentrations of tamoxifen, N-desmethyltamoxifen, 4-hydroxytamoxifen and endoxifen after a single dose and at steady-state conditions in virtual female patients. Further, the integration of known CYP2D6 enzyme activity differences for the phenotypes into the coupled tamoxifen-endoxifen PBPK model leads to the formation of differing endoxifen plasma concentrations at steady-state conditions as reported in literature.

Conclusions:

    A PBPK model was established that is able to describe the pharmacokinetics of tamoxifen, its two primary metabolites N-desmethyltamoxifen, 4-hydroxytamoxifen, and, most importantly, endoxifen at steady-state conditions in virtual female patients. Further, the model is able to describe the influence of CYP2D6 phenotypes on steady-state plasma concentrations of endoxifen.

    The coupled PBPK model will be used to further explore inter-individual variability in populations considering physiological variability, especially the influence of characteristic CYP2D6 phenotype distributions, in different geographical regions. Also, the model will allow an investigation of CYP2D6 inhibition on serum and tissue concentrations of endoxifen. Finally, the PK model can be extended to consider the mode of action in order to simulate tumor response with respect to tamoxifen and endoxifen serum and tissue concentrations influenced by CYP2D6 phenotypes and CYP2D6 inhibition in different virtual patient populations as outlined in [4]. References:

    [1] Hoskins JM, Carey LA, McLeod HL. CYP2D6 and tamoxifen: DNA matters in breast cancer. Nature Reviews Cancer. 2009 Aug; 9: 576-586

    [2] Jin Y, Desta Z, et al. CYP2D6 Genotype, Antidepressant Use, and Tamoxifen Metabolism During Adjuvant Breast Cancer Treatment. J Nat Canc Inst. 2005 Jan; 97(1): 30-39

    [3] Jordan VC. New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer. Steroids. 2007 Nov; 72(13): 829-842

    [4] Seruga B, Amir E. Cytochrome P450 2D6 and outcomes of adjuvant tamoxifen therapy: results of a meta-analysis. Breast Cancer Res Treat. 2010; 122: 609-617

    [4] Eissing T, Kuepfer L, et al. A computational systems biology software platform for multiscale modeling and simulation: Integrating whole-body physiology, disease biology, and molecular reaction networks. submitted.

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