Kristin Dickschen (1, 2), Thomas Eissing (1), Kirstin Thelen (1), Georg Hempel (2), Stefan Willmann (1)
(1) Bayer Technology Services, Computational Systems Biology, Leverkusen, Germany; (2) Westfälische Wilhelms-Universität, Münster, Germany
Objectives: Tamoxifen is a first-line agent in the treatment of estrogen-receptor positive breast cancer [1]. Endoxifen is a secondary metabolite of tamoxifen and regarded as a major contributor to its anti-tumoral activity [2]. Patients with the intermediate or poor metabolizer (IM, PM) phenotype of cytochrome P450 2D6 (CYP2D6), one major enzyme involved in biotransformation, exert a decrease in endoxifen steady-state plasma concentrations [3].
The impact of reduced CYP2D6 activity resulting in decreased endoxifen steady-state plasma concentration on treatment outcome remains to be elucidated [4]. However, there is evidence that IM and PM may not fully benefit from regular therapy [5].
Thus, a possible treatment strategy for IM and PM patients might be phenotype-guided dose escalation of tamoxifen to achieve endoxifen steady-state plasma concentrations comparable to extensive metabolizers (EM) [6].
Methods: A physiologically-based pharmacokinetics (PBPK)-model of endoxifen formation out of tamoxifen was developed for populations of European female individuals of EM, IM, and PM phenotype comprising physiological variability [7] and using prior knowledge of CYP2D6 activity [8].
The populations of PM and IM were adapted to a dose regimen of 4 months of 20mg tamoxifen daily followed by 4 months of 20mg tamoxifen twice daily [6]. Additionally, 4 months of 20mg tamoxifen daily followed by 4 months of 40mg tamoxifen once daily were simulated in both populations.
Results: Dose escalation from 20mg once daily to twice daily led to increased endoxifen steady-state plasma concentrations in both populations. However, only the IM population reached levels comparable to average EM endoxifen steady-state plasma concentrations.
Simulation experiments show that 40mg tamoxifen once daily achieved comparable results regarding plasma profiles to 20mg twice daily in both populations.
Conclusions: Dose escalation might prove a preferable treatment strategy for IM breast cancer patients, as model and experimental data [6], indicate comparable endoxifen steady-state plasma concentrations to EM. In terms of patient compliance, once daily 40mg is superior to twice daily 20mg.
Nevertheless, phenotype-guided dose escalation does not enable an exposure for PMs comparable to EMs up to doses of 60mg daily and may therefore not be the preferred dosing strategy. Possibly, direct endoxifen dosing to PM could be a suitable option of treatment. First-in-man studies have already been published [9].
References:
[1] Goetz, M.P., A. Kamal, and M.M. Ames, Tamoxifen pharmacogenomics: the role of CYP2D6 as a predictor of drug response. Clin Pharmacol Ther, 2008. 83(1): p. 160-6.
[2] Stearns, V., et al., Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst, 2003. 95(23): p. 1758-64.
[3] Jin, Y., et al., CYP2D6 Genotype, Antidepressant Use, and Tamoxifen Metabolism During Adjuvant Breast Cancer Treatment. Journal of the National Cancer Institute, 2005. 97(1): p. 30-39.
[4] Fleeman, N., et al., The clinical effectiveness and cost-effectiveness of genotyping for CYP2D6 for the management of women with breast cancer treated with tamoxifen: a systematic review. Health technology assessment (Winchester, England), 2011. 15(33): p. 1-102.
[5] Schroth, W., et al., Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen. JAMA, 2009. 302(13): p. 1429-36.
[6] Irvin, W.J., Jr., et al., Genotype-Guided Tamoxifen Dosing Increases Active Metabolite Exposure in Women With Reduced CYP2D6 Metabolism: A Multicenter Study. J Clin Oncol, 2011. 29(24): p. 3232-9.
[7] Willmann, S., et al., Development of a physiology-based whole-body population model for assessing the influence of individual variability on the pharmacokinetics of drugs. J Pharmacokinet Pharmacodyn, 2007. 34(3): p. 401-31.
[8] Coller, J.K., et al., The influence of CYP2B6, CYP2C9 and CYP2D6 genotypes on the formation of the potent antioestrogen Z-4-hydroxy-tamoxifen in human liver. Br J Clin Pharmacol, 2002. 54(2): p. 157-67.
[9] Ahmad, A., et al., Endoxifen, a new cornerstone of breast cancer therapy: demonstration of safety, tolerability, and systemic bioavailability in healthy human subjects. Clin Pharmacol Ther, 2010. 88(6): p. 814-7.
Reference: PAGE 21 (2012) Abstr 2421 [www.page-meeting.org/?abstract=2421]
Poster: Absorption and Physiology-Based PK