De wisselwerking tussen edoxaban en tamoxifen behandeling bij vrouwen met borstkanker

Rationale: Edoxaban is an oral direct factor Xa inhibitor which is widely used in patients with venous thromboembolism (VTE) or non-valvular atrial fibrillation. Recently, this agent has been shown to be non-inferior to low-molecular-weight heparin (LMWH) to prevent recurrent VTE in cancer patients. Edoxaban is also a substrate for P-glycoprotein (P-gp), a protein that excretes certain xenobiotics into the urine, faeces, and bile. Tamoxifen, an anti-estrogen drug used as adjuvant treatment in breast cancer patients, is a known P- gp inhibitor. Therefore, concomitant use of tamoxifen can potentially increase plasma levels of edoxaban and thereby increase the risk of bleeding. In this study, the effect of tamoxifen on the pharmacokinetics of edoxaban will be evaluated.
Objective: To compare the plasma concentration of edoxaban in women with breast cancer before and during treatment with tamoxifen.
Study design: An open-label, single-sequence crossover study
Study population: Women with breast cancer and an indication for tamoxifen as adjuvant or palliative therapy.
Intervention: Twenty-six breast cancer patients who are scheduled for adjuvant or palliative treatment with tamoxifen, will be given edoxaban 60 mg once daily for 4 days. On day 5, edoxaban will be stopped and tamoxifen therapy started. When steady-state of tamoxifen is reached after 28 days, edoxaban 60 mg once daily is given for 4 days concomitantly with ongoing tamoxifen therapy. At the fourth day of both edoxaban treatment periods, 4 blood samples (at 0, 1, 2, and 3 hours after ingestion) and one blood sample randomly taken in the time period 4 – 8 hours after ingestion will be collected.
Main study parameters/endpoints: a comparison between day 4 and 36 of edoxaban area under the plasma concenctration curve (AUC),maximum concentration (Cmax and several other coagulation, pharmacokinetic and pharmacodynamic parameters.
Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Patients will be seen in the hospital for inclusion and two times for a series of blood withdrawal on day 4 and 36. On days 4 and 36, patients have to be in the hospital for 4 hours. During these days, patients will get a venous cannula from which 4 blood samples will be taken per day over a time period of 3 hours. One sample will be obtained 4 to 8 hours after ingestion of edoxaban. Total volume of blood withdrawn is 54.6 ml per day. In this study, patients will use edoxaban, an anticoagulant drug. Patients may experience side effects of medication, such as hematomas. Based on previous studies with edoxaban, it is estimated that there is an individual risk of bleeding of 0.06% during this study. There is no individual benefit from participating in this study. However, the results may have clinical impact, because in patients with breast cancer, tamoxifen is the mainstay of adjuvant treatment, often for a period of 5 years, where patients may suffer from VTE. Therefore, information on the safety of this combination is important.

There is a minimal interaction between edoxaban and tamoxifen and it can safely be used concomitantly

Day 4: blood samples after four days of edoxaban use
Day 36: blood samples after four days of edoxaban use concomitantly with tamoxifen after steady state is reached

Twenty-six breast cancer patients who are scheduled for adjuvant or palliative treatment with tamoxifen, will be given edoxaban 60 mg once daily for 4 days. On day 5, edoxaban will be stopped and tamoxifen therapy started. When steady-state of tamoxifen is reached after 28 days, edoxaban 60 mg once daily is given for 4 days concomitantly with ongoing tamoxifen therapy. At the fourth day of both edoxaban treatment periods, 4 blood samples (at 0, 1, 2, and 3 hours after ingestion) and one blood sample randomly taken in the time period 4 – 8 hours after ingestion will be collected.