Focus of research
[Forschungslinie 2]: Pharmacometric data analysis
“Population pharmacogenetic/pharmacokinetic/pharmacodynamic modelling of tamoxifen therapy in breast cancer”
Tamoxifen is a widely used drug for the prevention and treatment of oestrogenreceptor (ER)-positive breast cancer. As a selective ER-modulator (SERM) tamoxifen acts as anti-oestrogen on tumour growth in breast tissue. It is considered as pro-drug which is metabolised by cytochrome P450 (CYP) enzymes to more active metabolites, among which, endoxifen is considered the most abundant and active metabolite. CYP2D6 and CYP3A4/5 are the major enzymes involved in endoxifen formation. The high polymorphic nature of CYP2D6 in humans has an impact on the extent of bioactivation of tamoxifen to endoxifen. Different studies have demonstrated the relationship of CYP2D6 phenotypes with lower endoxifen concentrations or investigated the relation to clinical outcome. However, contradictory results have been found and yet only limited quantitative knowledge on the clinical impact of CYP2D6 polymorphism and drug-drug interactions on tamoxifen pharmacokinetics is available.
The aim of my PhD project is to develop an integrated pharmacogenetic (PGx)/pharmaco- kinetic (PK)/pharmacodynamic (PD) model to quantitatively characterise the temporal profiles of tamoxifen and endoxifen. In addition, the impact of genetic variability on the formation of endoxifen will be assessed. As a second step, the relationship between endoxifen plasma concentrations and treatment response and clinical benefit from tamoxifen therapy will be evaluated and mathematically characterised. The final goal is to be able to exploit the full in silico model by simulations to optimise individual tamoxifen therapy.