Trial Information

The Effect of Antidepressants and Gabapentin on Tamoxifen Pharmacokinetics: A Prospective Study

OBJECTIVES:

- To examine the changes in the plasma concentrations of the hydroxylated metabolite,
4-hydroxy tamoxifen, and endoxifen in women with known or at high risk for developing
breast cancer who are receiving selective serotonin reuptake
inhibitor/serotonin-norepinephrine reuptake inhibitor therapy comprising venlafaxine,
citalopram hydrobromide, escitalopram oxalate, gabapentin, or sertraline hydrochloride
for the treatment of hot flashes, depression, or any other medically indicated
condition.

- To evaluate whether genetic variants known to affect the activity of CYP2D6, SULT1A1,
and other drug metabolizing enzymes (e.g., UGT's) involved in the biotransformation of
tamoxifen citrate affect the plasma concentrations of the hydroxylated metabolites,
4-hydroxy tamoxifen and endoxifen.

OUTLINE: This is a multicenter study.

Patients receive oral tamoxifen citrate and concurrent selective serotonin reuptake
inhibitor (SSRI)/serotonin-norepinephrine reuptake inhibitor (SNRI) therapy comprising oral
venlafaxine, citalopram hydrobromide, escitalopram oxalate, sertraline hydrochloride, or
gabapentin for 8-24 weeks. Treatment continues in the absence of disease progression.

Blood samples are obtained at baseline and after completion of study therapy. Samples are
evaluated by pharmacokinetic analysis to determine the effects of SSRI/SNRI study drugs on
plasma concentrations of tamoxifen and its metabolites. Plasma levels of tamoxifen citrate,
N-desmethyl tamoxifen, 4-OH tamoxifen, and endoxifen are measured using reverse phase high
performance liquid chromatography. Blood samples are also analyzed by CYP2D6 genotyping to
test for CYP2D6 gene variation (i.e., *3, *4, *6, *10, *17, and *41) in genes that encode
tamoxifen-metabolizing enzymes. Additional CYP2D6 alleles, including gene duplication and
gene deletion (*5) are assessed.