Clinical trial NCT00667121: Tamoxifen in Women With Breast Cancer and in Women at High-Risk of Breast Cancer Who Are Receiving Venlafaxine, Citalopram, Escitalopram, Gabapentin, or Sertraline
Official title: The Effect of Antidepressants and Gabapentin on Tamoxifen Pharmacokinetics: A Prospective Study
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Breast Cancer
Depression
Hot Flashes
Psychosocial Effects of Cancer and Its Treatment
Keywords: psychosocial effects of cancer and its treatment
breast cancer
hot flashes
depression
Lead sponsor: Mayo Clinic
Sponsor class: OTHER
First posted: 2008-04-25
Enrollment: 88
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_CONTROL
Time perspective: CROSS_SECTIONAL
Sampling method: PROBABILITY_SAMPLE
Study population: PATIENT CHARACTERISTICS:

* Menopausal status not specified
* Life expectancy ≥ 16 weeks
* No contraindication for venlafaxine, citalopram hydrobromide, escitalopram oxalate, gabapentin, or sertraline hydrochloride

PRIOR CONCURRENT THERAPY:

* See Disease Characteristics
* More than 4 weeks since prior and no concurrent medications that are known to inhibit the CYP2D6 system

Brief summary: RATIONALE: Studying samples of blood in the laboratory from patients receiving tamoxifen may help doctors learn more about the effects of other drugs on the level of tamoxifen in the blood.

PURPOSE: This clinical trial is studying levels of tamoxifen in the blood of women with breast cancer and in women at high risk of breast cancer who are receiving tamoxifen together with venlafaxine, citalopram, escitalopram, gabapentin, or sertraline.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* Prescribed tamoxifen either for the prevention or treatment of non-invasive or invasive breast cancer.
* Tamoxifen use \> 4 weeks without any breaks at a dose of 20 mg/day prior to registration
* to begin medical therapy with one of the following drugs: venlafaxine, citalopram, escitalopram, sertraline or gabapentin as determined by their physician
* Agree to continue tamoxifen during the proposed minimum study period of 8 weeks
* Willing to avoid known inhibitors of the CYP2D6 system for duration of study
* Ability to provide informed consent
* Willing to return to primary site of enrollment for follow-up
* Life expectancy \>= 16 weeks
* Agree to provide a blood specimen at the time of pre-treatment (baseline) and at follow-up

Exclusion Criteria:

* Contraindication to the use of venlafaxine, citalopram, escitalopram, gabapentin or sertraline.
* Use of medications that are known to inhibit the CYP2D6 system within 3 weeks of registration. (see appendix II for list)
* Known to be a CYP2D6 poor metabolizer (defined as homozygous for one of the following CYP2D6 null alleles: \*3, \*4, \*5, \*6).

  * Note: CYP2D6 genotyping is not required prior to enrollment; however, CYP2D6 genotyping will be performed at baseline and the treating physician will be notified of the results: all genotypic CYP2D6 PM will be replaced

Primary outcomes:
measure: Percent change in plasma concentrations of 4-hydroxy tamoxifen and of endoxifen after ≥ 8 weeks of concurrent administration of tamoxifen citrate and a CYP2D6 inhibitor
timeFrame: Between 8-16 weeks
Secondary outcomes:
Other outcomes:
Locations:
city: Indianapolis
country: United States
facility: Indiana University Melvin and Bren Simon Cancer Center
state: Indiana
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
state: Maryland
city: Ann Arbor
country: United States
facility: University of Michigan Comprehensive Cancer Center
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Chapel Hill
country: United States
facility: UNC Lineberger Comprehensive Cancer Center
state: North Carolina
city: Arlington
country: United States
facility: Virginia Cancer Specialists PC-Arlington
state: Virginia
Study officials:
affiliation: Mayo Clinic
name: Matthew P. Goetz, MD
role: STUDY_CHAIR
References: