Physiologically based pharmacokinetic modeling of tamoxifen and its metabolites in women of different CYP2D6 phenotypes provides new insight into the tamoxifen mass balance

Abstract

Tamoxifen is a first-line endocrine agent in the mechanism-based treatment of estrogen receptor positive (ER+) mammary carcinoma and applied to breast cancer patients all over the world. Endoxifen is a secondary and highly active metabolite of tamoxifen that is formed among others by the polymorphic cytochrome P450 2D6 (CYP2D6). It is widely accepted that CYP2D6 poor metabolizers exert a pronounced decrease in endoxifen steady-state plasma concentrations compared to CYP2D6 extensive metabolizers. Nevertheless, an in-depth understanding of the chain of cause and effect between CYP2D6 genotype, endoxifen steady-state plasma concentration, and subsequent tamoxifen treatment benefit still remains to be evolved. In this study, physiologically based pharmacokinetic (PBPK)-modeling was applied to mechanistically investigate the impact of CYP2D6 phenotype on endoxifen formation in female breast cancer patients undergoing tamoxifen therapy. A PBPK-model of tamoxifen and its pharmacologically important metabolites N-desmethyltamoxifen (NDM-TAM), 4-hydroxytamoxifen (4-OH-TAM), and endoxifen was developed and validated. This model is able to simulate the pharmacokinetics (PK) after single and repeated oral tamoxifen doses in female breast cancer patients in dependence of the CYP2D6 phenotype. A detailed model-based analysis of the mass balance offered support for a recent hypothesis stating a more prominent role for endoxifen formation from 4-OH-TAM. In the future this model provides a good basis to further investigate the linkage of PK, mode of action, and treatment outcome in dependence of factors such as phenotype, ethnicity, or co-treatment with CYP2D6 inhibitors.

Multigene and Drug Interaction Approach for Tamoxifen Metabolite Patterns Reveals Possible Involvement of CYP2C9, CYP2C19, and ABCB1

“…An ideal approach to evaluating the findings observed here would be through pharmacometric modeling and simulation studies. In fact, physiologically based pharmacokinetic modeling has been applied to tamoxifen wherein both CYP2D6 and CYP2C9 phenotypes affected concentrations of endoxifen and 4‐hydroxytamoxifen . Although these findings are consistent with our data, the modeling described by Dickschen et al did not consider the effects of multiple drug–drug interactions or other gene–drug interactions.…”

Clinically Relevant Concentrations of Anticancer Drugs: A Guide for Nonclinical Studies

“…One example of this is tamoxifen. Through the action of two cytochrome P450 oxidases (CYP2D6 and CYP3A4/5), three metabolites are produced with affinities for the estrogen receptor that are similar to or more potent than the parent molecule (24–27). In patients, these metabolites may be responsible for much of the pharmacodynamic action of the drug (24,25).…”

Applied Concepts in PBPK Modeling: How to Extend an Open Systems Pharmacology Model to the Special Population of Pregnant Women

“…In addition to that, CYP2A6 is a polymorphic enzyme complicating extrapolations from one group of individuals to another. Such issues could be addressed by further in vitro and/or well‐designed in vivo studies and pharmacogenomic information can also be reflected in the model …”