TY - JOUR
T1 - The Effect of Tamoxifen Dose Increment in Patients With Impaired CYP2D6 Activity
AU - Welzen, Marieke E. B.
AU - Dezentjé, Vincent O.
AU - van Schaik, Ron H. N.
AU - Colbers, Angela P. H.
AU - Guchelaar, Henk-Jan
AU - van Erp, Nielka P.
AU - den Hartigh, Jan
AU - Burger, David M.
AU - van Laarhoven, Hanneke W. M.
PY - 2015
Y1 - 2015
N2 - The effect of tamoxifen dose elevation on endoxifen serum concentration was investigated in patients with reduced CYP2D6 activity resulting from genetic variation and/or CYP2D6 inhibitor use. Additionally, baseline differences in endoxifen concentrations between the different CYP2D6 phenotypes were studied. Patients, treated with tamoxifen 20 mg once daily (QD) for at least 4 weeks, were classified as phenotypic extensive (EM), intermediate (IM), or poor (PM) metabolizer based on their genotype and comedication. In patients with an IM or PM phenotype, the tamoxifen dose was increased to 40 mg QD for 4 weeks. Tamoxifen, 4-OH-tamoxifen, N-desmethyltamoxifen, and endoxifen serum concentrations were measured at baseline and 4 weeks after the dose increment. Side effects of tamoxifen were assessed using the validated Functional Assessment of Cancer Therapy-Endocrine Symptom subscale (FACT-ESS-19). The median baseline endoxifen concentration differed between EMs (11.4 mcg/L: n = 19), IMs (8.3 mcg/L: n = 16), and PMs (4.0 mcg/L: n = 7), P = 0.040. Tamoxifen dose elevation significantly increased the median endoxifen concentrations in 12 IMs from 9.5 to 17.4 mcg/L (P < 0.001) and in 4 PMs from 3.8 to 7.8 mcg/L (P = 0.001), without influencing median FACT-ESS-19 scores. Raising the tamoxifen dose to 40 mg QD significantly increased endoxifen concentrations in IMs and PMs without increasing side effects. The tamoxifen dose increment in PMs was insufficient to reach endoxifen concentrations equal to those observed in EMs. Future studies will clarify the direct effect of endoxifen exposure on tamoxifen efficacy and may reveal a threshold endoxifen concentration that is critical for its efficacy
AB - The effect of tamoxifen dose elevation on endoxifen serum concentration was investigated in patients with reduced CYP2D6 activity resulting from genetic variation and/or CYP2D6 inhibitor use. Additionally, baseline differences in endoxifen concentrations between the different CYP2D6 phenotypes were studied. Patients, treated with tamoxifen 20 mg once daily (QD) for at least 4 weeks, were classified as phenotypic extensive (EM), intermediate (IM), or poor (PM) metabolizer based on their genotype and comedication. In patients with an IM or PM phenotype, the tamoxifen dose was increased to 40 mg QD for 4 weeks. Tamoxifen, 4-OH-tamoxifen, N-desmethyltamoxifen, and endoxifen serum concentrations were measured at baseline and 4 weeks after the dose increment. Side effects of tamoxifen were assessed using the validated Functional Assessment of Cancer Therapy-Endocrine Symptom subscale (FACT-ESS-19). The median baseline endoxifen concentration differed between EMs (11.4 mcg/L: n = 19), IMs (8.3 mcg/L: n = 16), and PMs (4.0 mcg/L: n = 7), P = 0.040. Tamoxifen dose elevation significantly increased the median endoxifen concentrations in 12 IMs from 9.5 to 17.4 mcg/L (P < 0.001) and in 4 PMs from 3.8 to 7.8 mcg/L (P = 0.001), without influencing median FACT-ESS-19 scores. Raising the tamoxifen dose to 40 mg QD significantly increased endoxifen concentrations in IMs and PMs without increasing side effects. The tamoxifen dose increment in PMs was insufficient to reach endoxifen concentrations equal to those observed in EMs. Future studies will clarify the direct effect of endoxifen exposure on tamoxifen efficacy and may reveal a threshold endoxifen concentration that is critical for its efficacy
U2 - https://doi.org/10.1097/FTD.0000000000000195
DO - https://doi.org/10.1097/FTD.0000000000000195
M3 - Article
C2 - 26192892
SN - 0163-4356
VL - 37
SP - 501
EP - 507
JO - Therapeutic drug monitoring
JF - Therapeutic drug monitoring
IS - 4
ER -