The threshold for endoxifen's beneficial effect has been reported to be 16 nM, since levels <16 nM have been associated with a 26% lower disease-free survival rate compared with BC patients with levels >16 nM. However, it is estimated that the standard dose of tamoxifen 20 mg once daily results in an endoxifen level of <16 nM in about one-fifth to one-quarter of women, potentially exposing these women to risk of disease recurrence.
Only about 40% of the variability in endoxifenÕs concentrations may be explained by the CYP2D6 genotype. Other factors, such as drug-drug interactions, dietary or food supplements, medication adherence, age, BMI, hormonal status, and circadian rhythm, are all thought to affect endoxifen levels.
A prospective open-label intervention study, TOTAM (TDM Of TAMoxifen), was conducted to determine the feasibility of increasing the proportion of tamoxifen users who reach the prespecified endoxifen threshold concentration of 16 nM using therapeutic drug monitoring (TDM).
This study enrolled women who were treated with tamoxifen 20 mg daily for early BC. It excluded those who were receiving tamoxifen for >3 months, received a starting dose of tamoxifen of >20 mg daily, had a prior diagnosis of endometrial cancer (within the past 3 years), or had a diagnosis of advanced or metastatic BC.
Patients were assessed at 3, 4.5, and 6 months after initiation of tamoxifen therapy for the presence of comedications or supplements, occurrence of adverse events, adherence (using the Morisky Medication Adherence Scale), and endoxifen levels. If endoxifen levels were <16 nM, the patient was adherent, and was not experiencing a drug-drug interaction, the dose of tamoxifen was increased. Patients with an endoxifen level of 12 to <16 had their dose of tamoxifen increased to 30 mg daily, and those with levels <12 nM had their dose adjusted to 40 mg daily. CYP2D6 genotyping was also performed.
Patients were classified as ultrarapid metabolizers (UM), extensive or normal metabolizers (EM), intermediate metabolizers (IM), or poor metabolizers (PM). A subgroup analysis was also conducted examining the effect of age (age 45 years or younger or age 55 years or older) on endoxifen exposure.
Between January 2018 and June 2019, 145 women with early BC were enrolled in the trial. Of these women, nine patients were switched to an aromatase inhibitor due to subtherapeutic endoxifen concentrations (n = 5) or tamoxifen adverse events (n = 4).
The mean age of the study population was 57 years. Three months after tamoxifen initiation, 21% (n = 30) had an endoxifen level <16 nM. Of these "subtherapeutic" patients, 27 had their tamoxifen dose increased to 30 or 40 mg daily; three of the patients' prescribers did not increase their dose. Overall, the mean endoxifen level was 27.7 nM. At the 4.5-month follow-up, 18 patients had an endoxifen level <16 nM, including six patients receiving 20 mg daily, three patients on 30 mg daily, and nine patients on 40 mg daily.
By 6 months, 89% had endoxifen levels >16 nM with TDM-guided dose individualization. Of the 11% (n = 15) of patients whose endoxifen levels were <16 nM, eight were receiving tamoxifen 20 mg daily and seven were on 40 mg of tamoxifen daily. In total, during the first 6 months, 31 patients had their dose of tamoxifen increased to 30 or 40 mg daily.
At 3 months, all of the patients who were CYP2D6 PMs had endoxifen levels <16 nM compared with only 7% of EMs. Age and BMI did not affect endoxifen concentrations. Tamoxifen dose escalation was not associated with an increased risk of adverse effects.
As drug experts, pharmacists are well versed in TDM. Although this study did not correlate endoxifen levels with clinical outcome, it describes a potential tool that be used to help patients achieve optimal benefit from tamoxifen therapy. Further research is needed.
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