Hormonal status affects plasma exposure of tamoxifen and its main metabolites in tamoxifen-treated breast cancer patients

João Paulo Bianchi Ximenez,Maria Paula Marques,Jurandyr Moreira De Andrade,Eduardo Barbosa Coelho,Guilherme Suarez-Kurtz,Vera Lucia Lanchote

doi:10.1186/s40360-019-0358-y

João Paulo Bianchi Ximenez, Maria Paula Marques + Show 4 more

Open Access

https://doi.org/10.1186/s40360-019-0358-y

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Abstract

BackgroundTamoxifen is considered a prodrug of its active metabolite endoxifen, which is dependent on the CYP2D6 and CYP3A enzymes. Tamoxifen pharmacokinetic variability influences endoxifen exposure and, consequently, its clinical outcome. This study investigated the impact of hormonal status on the pharmacokinetics of tamoxifen and its metabolites in TAM-treated breast cancer patients.MethodsTAM-treated breast cancer patients (n = 40) previously believed to have CYP3A activity within the normal range based on oral midazolam and phenotyped as CYP2D6 normal metabolizers using oral metoprolol were divided into two groups according to premenopausal (n = 20; aged 35–50 years) or postmenopausal (n = 20; aged 60–79 years) status. All patients were treated with 20 mg/day tamoxifen for at least three months. Serial plasma samples were collected within the 24 h dose interval for analysis of unchanged tamoxifen, endoxifen, 4-hydroxytamoxifen and N-desmethyltamoxifen quantified by LC-MS/MS. CYP activities were assessed using midazolam apparent clearance (CYP3A) and the metoprolol/alfa-hydroxymetoprolol plasma metabolic ratio (CYP2D6). CYP3A4, CYP3A5 and CYP2D6 SNPs and copy number variation were investigated using TaqMan assays.ResultsPostmenopausal status increased steady-state plasma concentrations (Css) of tamoxifen (116.95 vs 201.23 ng/mL), endoxifen (8.01 vs 18.87 ng/mL), N-desmethyltamoxifen (485.16 vs 843.88 ng/mL) and 4-hydroxytamoxifen (2.67 vs 4.11 ng/mL). The final regression models included hormonal status as the only predictor for Css of tamoxifen [β-coef ± SE, p-value (75.03 ± 17.71, p = 0.0001)] and 4-hydroxytamoxifen (1.7822 ± 0.4385, p = 0.0002), while endoxifen Css included hormonal status (8.578 ± 3.402, p = 0.02) and race (11.945 ± 2.836, p = 0.007). For N-desmethyltamoxifen Css, the final model was correlated with hormonal status (286.259 ± 76.766, p = 0.0007) and weight (− 8.585 ± 3.060, p = 0.008).ConclusionThe premenopausal status was associated with decreased endoxifen plasma concentrations by 135% compared to postmenopausal status. Thus, the endoxifen plasma concentrations should be monitored mainly in the premenopausal period to maintain plasma levels above the efficacy threshold value.Trial registrationRBR-7tqc7k.

Highlights

Tamoxifen is considered a prodrug of its active metabolite endoxifen, which is dependent on the CYP2D6 and CYP3A enzymes
This study investigates the influence of menopausal status on the pharmacokinetics of TAM and its metabolites END, 4-HTAM and NDTAM in TAM-treated breast cancer patients phenotyped as normal metabolizers (NM) for CYP2D6 and with CYP3A activity based on the oral midazolam clearance
All patients were histologically diagnosed with estrogen receptor (ER)-positive breast cancer, and the clinical diagnosis of menopause was based on menstrual history, ultrasound features and age

Summary

Introduction

Tamoxifen is considered a prodrug of its active metabolite endoxifen, which is dependent on the CYP2D6 and CYP3A enzymes. Tamoxifen pharmacokinetic variability influences endoxifen exposure and, its clinical outcome. This study investigated the impact of hormonal status on the pharmacokinetics of tamoxifen and its metabolites in TAM-treated breast cancer patients. Tamoxifen (TAM) has been used for more than 40 years to treat early breast cancer and metastatic breast cancer in either preoperative or postoperative adjuvant therapy. 5-year TAM therapy almost halves the annual risk of breast cancer recurrence and decreases the breast cancer mortality incidence by one-third in pre- and postmenopausal patients [2]. The TAM anticancer effect is due to its two active metabolites, 4-hydroxytamoxifen (4-HTAM) and endoxifen (END), which have a 100-fold higher antiestrogenic effect than the parent drug [3]. There is considerable concern regarding END exposure variability and treatment outcome [4]

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