Clinical pharmacokinetics and pharmacogenetics of tamoxifen and endoxifen

ABSTRACT

Introduction: Tamoxifen dominates the anti-estrogenic therapy in the early and metastatic breast cancer setting. Tamoxifen has a complex metabolism, being mainly metabolized by CYP2D6 into its 30–100 times more potent metabolite, endoxifen. Recently, a phase I study in which endoxifen as an orally z-endoxifen hydrochloride has been successfully evaluated.

Areas covered: the principal pharmacogenetic and non-genetic differences in the pharmacology of tamoxifen and endoxifen are evaluated. To this end, references from PubMed, Embase or Web of Science, among others, were reviewed As non-genetic factors, important differences and similarities such age, or adherence to tamoxifen therapy are comprehensively illustrated. Additionally, since CYP2D6 genotypes are considered the main limitation of tamoxifen, many studies have investigated the association between the worsened clinical outcomes in patients with non-functional CYP2D6 genotypes. In this review, an overview of the research on this field is presented. Also, a summary describing the literature about individualizing tamoxifen therapy with endoxifen concentrations and its limitations is listed.

Expert opinion: z-endoxifen hydrochloride is only investigated in the metastatic setting, still more research is required before its place in therapeutics is known. Similarly, monitoring tamoxifen efficacy based on endoxifen concentrations might not be overall recommended due to the limited evidence available.

KEYWORDS:

• Breast cancer
• endocrine therapy
• endoxifen
• pharmacogenetics
• pharmacokinetics
• tamoxifen
• therapeutic drug monitoring

Article highlights

• For more than 40 years, tamoxifen has been successfully prescribed in the adjuvant and metastatic setting, however, a great variation between patients is still observed

• Tamoxifen also has a complicated metabolism, mainly metabolized by CYP2D6 into its 30-100 times more potent, endoxifen.

• Endoxifen is currently investigated as an orally form of z-endoxifen hydrochloride in the metastatic scenario.

• Therapeutic drug monitoring based on endoxifen concentration levels has been hypothesized to be the best approach for individualizing tamoxifen efficacy, still little evidence is currently available.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.