How often did Belgian physicians co-prescribe tamoxifen with strong CYP2D6 inhibitors over the last 6 years?
Aims: Tamoxifen is widely used in the treatment of breast cancer. It is a pro-drug metabolized to the more active endoxifen through CYP2D6. Concomitant intake of CYP2D6 inhibitors results in lower endoxifen levels and could influence efficacy. The objective of this study was to evaluate the evolution of co-prescription of tamoxifen and CYP2D6 inhibitors in Belgium. Methods: Data were retrieved from the Pharmanet database of the National Institute for Health and Disability Insurance for the period January 2006-December 2009. For the analysis of the evolution of the co-prescription, the period was divided in subperiods of 2 months. The category tamoxifen+CYP2D6 inhibitor was defined as women who were delivered tamoxifen and a CYP2D6 inhibitor in that subperiod. The results were validated on the period December 2011-May 2012. Results: The percentage of co-prescription decreased over time for the strong CYP2D6 inhibitors and increased for the weak CYP2D6 inhibitor, with these trends persisting in 2012. Tamoxifen and CYP2D6 inhibitors were mostly prescribed by general practitioners and gynaecologists and by general practitioners and psychiatrists, respectively. Discussion: This study shows that a proportion of women taking tamoxifen in Belgium are prescribed a strong CYP2D6 inhibitor, which could affect tamoxifen efficacy. Over time, the concomitant intake decreased. Paroxetine was the most prescribed strong CYP2D6 inhibitor. Venlafaxine, a weak CYP2D6 inhibitor, was prescribed more often. This study also shows that tamoxifen and the CYP2D6 inhibitors are not only prescribed by physicians specialized in breast cancer; therefore, all physicians should be aware of this interaction.
[Show abstract] [Hide abstract] ABSTRACT: The clinical usefulness of assessing the enzymatic activity of CYPD6 in patients taking tamoxifen had been longly debated. In favor of preemptive evaluation of phenotypic profile of patients is the strong pharmacologic rationale, being that the formation of endoxifen the major and clinically most important metabolite of tamoxifen, is largely dependent on the activity of CYP2D6. This enzyme is highly polymorphic enzyme for which the activity is largely depending on genetics, but. that can also be inhibited by a number of drugs, i.e. antidepressants, which are frequently used in patients with cancer. Unfortunately, the clinical trials that have been published in that last years are contradicting each other on the association between CYP2D6 and significant clinical endpoints, and for this reason CYP2D6 genotyping is at present not generally recommended. Despite this, the CYP2D6 genotyping test for tamoxifen is available in many laboratories and it may still be an appropriate test to use it in specific cases.0Comments 0Citations
- "During the period, the co-prescription of fluoxetine and paroxetine decreased, while the co-prescription of venlafaxine increased over time as well. General practitioners, followed by psychiatrists , internists (including oncologists), and gynaecologists are the major prescribers and, interestingly, gynaecologists and psychiatrists prescribed more venlafaxine and less paroxetine than general practitioners and internists, suggesting the need to disseminate the knowledge of drug–drug interactions to all medical professionals to minimize the risk of deleterious drug interactions that may reduce the effectiveness of treatment with tamoxifen  (Table 4). "
- [Show abstract] [Hide abstract] ABSTRACT: Pharmacogenetics aims to use the patients’ genetic information in order to treat diseases more efficiently and minimize adverse events. The hereon based concept of Individualized Treatment finds its origin in associations of genetic information with treatment outcome. In this chapter a selection of gene-drug associations are summarized providing details on the underlying mechanisms, the clinical significance, and the current status of clinical implementation. The first example is the association between CYP2D6 and tamoxifen in the treatment of ER-positive breast cancer. A brief summary on the historical development of this research question provides insights in the strengths and difficulties of pharmacogenetics findings. In the context of the summary on the gene-drug association CYP2C19/clopidogrel the difficulties of the clinical implementation process, which have to be encountered, when including genetic testing in the every-day health care are mentioned. However, pharmacogenetics is not only a part of the post-marketing optimization of treatment outcome, but also plays an important role in drug development. Indeed, there are several examples where genetic findings were prerequisite for the following drug development and clinical approval. In this chapter the development of CCR5 antagonists and inhibitors of the bcr-abl tyrosine kinase are summarized. Finally, the novel drug ivacaftors, a drug specifically approved for a genetically defined minority of patients with cystic fibrosis, is mentioned in the context of pharmacogenetics.0Comments 0Citations
- [Show abstract] [Hide abstract] ABSTRACT: Clinical response to tamoxifen varies widely among women treated with this drug for hormone receptor-positive breast cancer. The principal active metabolite – endoxifen – is generated through hepatic metabolism of tamoxifen, with key roles for cytochrome P450 (CYP) CYP2D6 and CYP3A. By influencing endoxifen formation, genetic variants of CYP2D6 may affect response to tamoxifen. After a decade of research, examining the effects of CYP2D6 genetic variants on tamoxifen efficacy, there is still no agreement on the clinical utility of CYP2D6 genotype as biomarker for the prediction of breast cancer outcome, because studies revealed conflicting results. However, tamoxifen metabolism is complex and involves several other drug-metabolizing enzymes. Genetic variants of other CYP enzymes, including CYP3A4 and CYP2C9/19, as well as co-medication interfering with the metabolic activity of CYP2D6 and CYP3A4 have been shown to affect endoxifen concentrations and may also contribute to the variability in response to tamoxifen. Phenotyping strategies can predict endoxifen exposure more accurately than CYP2D6 genotype, but do not take into account all factors influencing endoxifen exposure. Therapeutic drug monitoring (TDM) is likely to be the optimal strategy for individualization of tamoxifen treatment. According to a growing amount of literature, endoxifen concentration seems to be a predictor of clinical outcome. The relationship between endoxifen levels and breast cancer outcomes has to be replicated and confirmed and the value of TDM should be evaluated in prospective clinical trials. Caution is advised regarding the concomitant use of medications which could interact with tamoxifen, including inhibitors and inducers of CYP enzymes.0Comments 11Citations