Open-Label Drug Interaction Study Evaluating Desvenlafaxine Succinate Sustained Release (DVS SR) 100mg On The Pharmacokinetics Of Tamoxifen When Coadministered To Healthy Post-Menopausal Female Subjects

Pfizer30 enrolled

Overview

The goal of this study is to evaluate the effect of multiple doses of Desvenlafaxine SR on the pharmacokinetics of Tamoxifen and endoxifen when coadministered to healthy post-menopausal female subjects. This study will also evaluate the safety and tolerability of Desvenlafaxine SR and Tamoxifen when coadministered to healthy post-menopausal female subjects.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

NONE

Enrollment

Conditions

Pharmacokinetics

Interventions

TamoxifenDRUG

Period 1-Tamoxifen 40mg on study day 1.

Tamoxifen and Desvenlafaxine Succinate Sustained ReleaseDRUG

Period 2-Desvenlafaxine SR 100mg on days 1-28 with coadministration of Tamoxifen 40mg on day 7.

Eligibility

Sex: FEMALEMin age: 45 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: * Healthy post-menopausal female subjects, at least 45 years of age, with confirmed post-menopausal status * Hysterectomized subjects * Body Mass Index (BMI) less than or equal to 34.0 kg/m2 * Nonsmoker or smoker of fewer than 5 cigarettes per day as determined by history * An informed consent document signed and dated by the subject Exclusion Criteria: * History of significant blood, kidney, endocrine, lung, gastrointestinal, heart, liver, psychiatric, neurologic, or allergic disease * Presence or history of deep vein thrombosis or transient ischemic attack * History of seizure disorder * Presence or history of glaucoma or increased intraocular pressure * Allergy to or unable to tolerate tamoxifen, desvenlafaxine, or venlafaxine * History of substance abuse within 1 year of study * A positive urine drug screen * Treatment with an investigational drug within 30 days * Consumption of grapefruit or grapefruit related citrus fruits * 12 lead ECG demonstrating QTc \>450 msec at screening * Pregnant or nursing females * Use of prescription or nonprescription drugs and dietary supplements * History of sensitivity to heparin or heparin induced thrombocytopenia * Severe acute or chronic medical or psychiatric condition or laboratory abnormality * Use of CYP 2D6 inhibitors and CYP 3A4 inhibitors/inducers

Locations (2)

Pfizer Investigational Site

Miami, Florida, United States

Pfizer Investigational Site

Miami, Florida, United States

Outcomes

Primary Outcomes

Tamoxifen Area Under the Plasma Concentration-time Profile From Time 0 Extrapolated to Infinite Time (AUCinf) Following Tamoxifen Alone and When Coadministered With DVS SR

Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It is obtained from AUC (0 - t) plus AUC (t - ∞); measured as nanograms multiplied by hours divided by milliliters (ng\*hr/mL).

Time frame: Period 1 / Day 1: 0, 0.5, 1, 2, 3, 4, 6, 8, 12,16, 24, 48, 72, 120, 168, 216, 264, 312, 384, 456, and 528 hours after dosing; Period 2 / Day 1 and Day 7: 0, 0.5, 1, 2, 3, 4, 6, 8, 12 and 16 hours; 0 hour on Day 8, 9, 10, 12, 14, 16, 18, 20, 23, 26 and 29.

Endoxifen (Metabolite) Area Under the Plasma Concentration-time Profile From Time 0 Extrapolated to Infinite Time (AUCinf) Following Endoxifen Alone and When Coadministered With DVS SR

Endoxifen is a metabolite of Tamoxifen. Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It is obtained from AUC (0 - t) plus AUC (t - ∞).

Secondary Outcomes

Tamoxifen Maximum Observed Concentration (Cmax) Following Tamoxifen Alone and When Coadministered With DVS SR

Cmax measured as nanograms per milliliters (ng/mL).

Tamoxifen Time for Cmax (Tmax) Following Tamoxifen Alone and When Coadministered With DVS SR

Time for maximum observed plasma concentration.

Data from ClinicalTrials.gov

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Tamoxifen Terminal Half-life (t 1/2) Following Tamoxifen Alone and When Coadministered With DVS SR

Terminal half-life is the time measured for the plasma concentration to decrease by one half.

Tamoxifen Apparent Clearance (CL/F) Following Tamoxifen Alone and When Coadministered With DVS SR

Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood calculated as (Dose/AUCinf); measured as milliliters per minute (mL/min).

Tamoxifen Apparent Volume of Distribution (Vz/F) Following Tamoxifen Alone and When Coadministered With DVS SR

Calculated as Dose / (AUCinf \* kel); where kel=terminal phase rate constant.

Endoxifen (Metabolite) Maximum Observed Concentration (Cmax) Following Tamoxifen Alone and When Coadministered With DVS SR

Endoxifen (Metabolite) Time for Cmax (Tmax) Following Tamoxifen Alone and When Coadministered With DVS SR

Time for maximum observed plasma concentration.

Endoxifen (Metabolite) Terminal Half-life (t 1/2) Following Tamoxifen Alone and When Coadministered With DVS SR

Terminal half-life is the time measured for the plasma concentration to decrease by one half.

Endoxifen (Metabolite) Apparent Clearance (CL/F) Following Tamoxifen Alone and When Coadministered With DVS SR

Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood calculated as (Dose/AUCinf); measured as milliliters per minute (mL/min).

Endoxifen (Metabolite) Apparent Volume of Distribution (Vz/F) Following Tamoxifen Alone and When Coadministered With DVS SR

N-desmethyl-tamoxifen (Metabolite) Area Under the Plasma Concentration-time Profile From Time 0 Extrapolated to Infinite Time (AUCinf) Following Tamoxifen Alone and When Coadministered With DVS SR

N-desmethyl-tamoxifen is a metabolite of Tamoxifen. Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It is obtained from AUC (0 - t) plus AUC (t - ∞).

N-desmethyl-tamoxifen (Metabolite) Maximum Observed Concentration (Cmax) Following Tamoxifen Alone and When Coadministered With DVS SR

N-desmethyl-tamoxifen (Metabolite) Time for Cmax (Tmax) Following Tamoxifen Alone and When Coadministered With DVS SR

Time for maximum observed plasma concentration.

N-desmethyl-tamoxifen (Metabolite) Terminal Half-life (t 1/2) Following Tamoxifen Alone and When Coadministered With DVS SR

Terminal half-life is the time measured for the plasma concentration to decrease by one half.

N-desmethyl-tamoxifen (Metabolite) Apparent Clearance (CL/F) Following Tamoxifen Alone and When Coadministered With DVS SR

Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood calculated as (Dose/AUCinf); measured as milliliters per minute (mL/min).

N-desmethyl-tamoxifen (Metabolite) Apparent Volume of Distribution (Vz/F) Following Tamoxifen Alone and When Coadministered With DVS SR

4-hydroxy-tamoxifen (Metabolite) Area Under the Plasma Concentration-time Profile From Time 0 Extrapolated to Infinite Time (AUCinf) Following Tamoxifen Alone and When Coadministered With DVS SR

4-hydroxy-tamoxifen is a metabolite of Tamoxifen. Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It is obtained from AUC (0 - t) plus AUC (t - ∞).

4-hydroxy-tamoxifen (Metabolite) Maximum Observed Concentration (Cmax) Following Tamoxifen Alone and When Coadministered With DVS SR

4-hydroxy-tamoxifen (Metabolite) Time for Cmax (Tmax) Following Tamoxifen Alone and When Coadministered With DVS SR

Time for maximum observed plasma concentration.

4-hydroxy-tamoxifen (Metabolite) Terminal Half-life (t 1/2) Following Tamoxifen Alone and When Coadministered With DVS SR

Terminal half-life is the time measured for the plasma concentration to decrease by one half.

4-hydroxy-tamoxifen (Metabolite) Apparent Clearance (CL/F) Following Tamoxifen Alone and When Coadministered With DVS SR

Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood calculated as (Dose/AUCinf); measured as milliliters per minute (mL/min).

4-hydroxy-tamoxifen (Metabolite) Apparent Volume of Distribution (Vz/F) Following Tamoxifen Alone and When Coadministered With DVS SR

Plasma Tamoxifen Concentration Versus Time Summary: Tamoxifen Alone and When Coadministered With DVS SR

Summary statistics were to be calculated by setting concentration values below the lower limit of quantification (LLQ = 0.250 ng/mL) to zero. Summary statistics were not to be presented if number of observations above lower limit of quantification (NALQ) = 0.

Time frame: Period 1 / Day 1 and Period 2 / Day 1: 0, 0.5, 1, 2, 3, 4, 6, 8, 12,16, 24, 48, 72, 120, 168, 216, 264, 312, 384, 456, and 528 hours after dosing

Plasma Endoxifen (Metabolite) Concentration Versus Time Summary: Tamoxifen Alone and When Coadministered With DVS SR

Summary statistics were to be calculated by setting concentration values below the lower limit of quantification (LLQ = 0.100 ng/mL) to zero. Summary statistics were not to be presented if number of observations above lower limit of quantification (NALQ) = 0.

Time frame: Period 1 / Day 1 and Period 2 / Day 1: 0, 0.5, 1, 2, 3, 4, 6, 8, 12,16, 24, 48, 72, 120, 168, 216, 264, 312, 384, 456, and 528 hours after dosing

Plasma N-desmethyl-tamoxifen (Metabolite) Concentration Versus Time Summary: Tamoxifen Alone and When Coadministered With DVS SR

Time frame: Period 1 / Day 1 and Period 2 / Day 1: 0, 0.5, 1, 2, 3, 4, 6, 8, 12,16, 24, 48, 72, 120, 168, 216, 264, 312, 384, 456, and 528 hours after dosing

Plasma 4-hydroxy-tamoxifen (Metabolite) Concentration Versus Time Summary: Tamoxifen Alone and When Coadministered With DVS SR

Time frame: Period 1 / Day 1 and Period 2 / Day 1: 0, 0.5, 1, 2, 3, 4, 6, 8, 12,16, 24, 48, 72, 120, 168, 216, 264, 312, 384, 456, and 528 hours after dosing