Official Title: “The Effect of Antidepressants and Gabapentin on Tamoxifen Pharmacokinetics: A Prospective Study”

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.

Study Type: Interventional

Study Design: Treatment

Study Primary Completion Date: July 2009

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.

Intervention(s) in this Clinical Trial

• Drug: citalopram hydrobromide
• Drug: escitalopram oxalate
• Drug: gabapentin
• Drug: sertraline hydrochloride
• Drug: tamoxifen citrate
• Drug: venlafaxine
• Genetic: molecular genetic technique
• Other: high performance liquid chromatography
• Other: laboratory biomarker analysis
• Other: pharmacological study
• Procedure: adjuvant therapy

Primary Measures

• 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
  • Safety Issue?: No

DISEASE CHARACTERISTICS:

• Meets 1 of the following criteria:
• Diagnosis of invasive or non-invasive breast cancer
• At high risk for developing breast cancer
• Has been receiving tamoxifen citrate for at least 4 weeks without any breaks either for the prevention or the adjuvant treatment of invasive or non-invasive breast cancer at a dose of 20 mg/day
• Planning to begin medical therapy with one of the following drugs, as determined by physician:
• Venlafaxine
• Citalopram hydrobromide
• Escitalopram oxalate
• Sertraline hydrochloride
• Gabapentin
• Agrees to continue tamoxifen citrate during the proposed minimum study period of 8 weeks
• Known CYP2D6 genotype
• Not known to be a CYP2D6 poor metabolizer (defined as homozygous for one of the following CYP2D6 null alleles: *3, *4, *5, *6) as determined from the baseline genotype test
• Estrogen receptor-positive disease (for patients with breast cancer)

PATIENT CHARACTERISTICS:

• Menopausal status not specified
• Life expectancy ≥ 16 weeks
• Willing to return to primary site of enrollment for follow-up, including any of the following:
• Mayo Clinic Rochester
• Indiana University
• University of Michigan
• Johns Hopkins
• 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

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Mayo Clinic

Overall Clinical Trial Officials and Contacts

Matthew P. Goetz, MD Study Chair Mayo Clinic  

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00667121

Study ID Number: CDR0000585065

ClinicalTrials.gov Identifier: NCT00667121

Health Authority: Unspecified

Clinical trial summary from the National Cancer Institute's PDQ® database