Healthy
Conditions
Keywords
Healthy Subjects
Brief summary
The purpose of this study is to determine if the relative difference in Pharmacokinetics (PK) between extensive metabolizers (EMs) and poor metabolizers (PMs) is the same with desvenlafaxine SR and venlafaxine ER when a single dose is administered.
Interventions
DRUGVenlafaxine Extended Release (VEN ER)
Sponsors
Wyeth is now a wholly owned subsidiary of Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy men and women aged 18 to 55 years. Healthy as determined by the investigator on the basis of medical history and physical examination, laboratory test results, vital signs, and 12-lead electrocardiogram (ECG). * History of being a nonsmoker for at least 1 year. * Subjects have to be either extensive CYP2D6 metabolizers with a normal complement of 1 or 2 fully active enzyme gene alleles or poor CYP2D6 metabolizers (lack of active enzyme gene alleles) via genetic testing of a blood sample.
Exclusion criteria
* Presence or history of any significant cardiovascular, hepatic, renal, respiratory, gastrointestinal, endocrine, immunologic, dermatologic, hematologic, neurologic, or psychiatric disease or any severe conditions of the ears, eyes or throat (such as glaucoma or increased intraocular pressure). * Known or suspected alcohol abuse or consumption of more than 2 standard units per day (a standard unit equals 12 ounces of beer, 1½ ounces of 80-proof alcohol, or 6 ounces of wine) within the past 6 months. * Known or suspected current abuse of prohibited drugs or other substances. Use of any hormonal therapy within 30 days before study day -1 until the end of the partial inpatient confinement period.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Concentration (Cmax) of Venlafaxine After Single Dose of Venlafaxine Extended-release (VEN ER) by Metabolizer Status | single dose | Cmax is a measure of drug metabolism and presented as least squares geometric mean with 90% Confidence Interval. Variations in drug metabolism among individuals can be due to differences in genetic expression (phenotype) of Cytochrome P450 (CYP450) enzymes. Enzyme CYP2D6 has 4 metabolizer phenotypes: poor (PM), intermediate (IM), extensive (EM), and ultrarapid (UM) metabolizers. |
| Area Under the Concentration-time Curve (AUC) of Venlafaxine After Single Dose of VEN ER by Metabolizer Status | single dose | AUC is drug level over time and measures drug metabolism. Variations in drug metabolism among individuals can be due to differences in genetic expression (phenotype) of Cytochrome P450 (CYP450) enzymes. Enzyme CYP2D6 has 4 metabolizer phenotypes: poor (PM), intermediate (IM), extensive (EM), ultrarapid (UM) metabolizers. |
| Maximum Concentration (Cmax) of Desvenlafaxine After Single Dose of VEN ER by Metabolizer Status | single dose | Cmax is a measure of drug metabolism. Variations in drug metabolism among individuals can be due to differences in genetic expression (phenotype) of Cytochrome P450 (CYP450) enzymes. Enzyme CYP2D6 has 4 metabolizer phenotypes: poor (PM), intermediate (IM), extensive (EM), and ultrarapid (UM) metabolizers. |
| Area Under the Concentration-time Curve (AUC) of Desvenlafaxine After Single Dose of VEN ER by Metabolizer Status | single dose | AUC is drug level over time and measures drug metabolism. Variations in drug metabolism among individuals can be due to differences in genetic expression (phenotype) of Cytochrome P450 (CYP450) enzymes. Enzyme CYP2D6 has 4 metabolizer phenotypes: poor (PM), intermediate (IM), extensive (EM), ultrarapid (UM) metabolizers. |
| Maximum Concentration (Cmax) of Desvenlafaxine After Single Dose of Desvenlafaxine Succinate Sustained-Release (DVS SR) by Metabolizer Status | single dose | Cmax is a measure of drug metabolism and is presented as least squares geometric mean with 90% Confidence Interval.Variations in drug metabolism among individuals can be due to differences in genetic expression (phenotype) of Cytochrome P450 (CYP450) enzymes. Enzyme CYP2D6 has 4 metabolizer phenotypes: poor (PM), intermediate (IM), extensive (EM), and ultrarapid (UM) metabolizers. |
| Area Under the Concentration-time Curve (AUC) of Desvenlafaxine After Single Dose of DVS SR by Metabolizer Status | single dose | AUC is drug level over time and measures drug metabolism. Variations in drug metabolism among individuals can be due to differences in genetic expression (phenotype) of Cytochrome P450 (CYP450) enzymes. Enzyme CYP2D6 has 4 metabolizer phenotypes: poor (PM), intermediate (IM), extensive (EM), ultrarapid (UM) metabolizers. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited in the United States from June 2008 to August 2008.
Pre-assignment details
Participants were screened for cytochrome P450 2D6 (CYP2D6) genotype to identify 7 extensive metabolizers and 7 poor metabolizers (inclusion criteria). Eligible participants were then randomly assigned to a sequence group.
Participants by arm
| Arm | Count |
|---|---|
| Sequence Group A Day 1: single 50mg oral dose of Desvenlafaxine Succinate Sustained Release (DVS SR) in a fasting state. Days 1-6: 120 hours of PK sampling. Days 7-10: Wash out period. Day 11: single 75mg oral dose of Venlafaxine ER (VEN ER) in a fasting state. Day 11-16: 120 hours of PK sampling. | 7 |
| Sequence Group B Day 1: single 75mg oral dose of Venlafaxine Extended Release (VEN ER) in a fasting state. Days 1-6: 120 hours of PK sampling. Days 7-10: Wash out period. Day 11: single 50mg oral dose of Desvenlafaxine Succinate Sustained Release (DVS SR) in a fasting state. Day 11-16: 120 hours of PK sampling. | 7 |
| Total | 14 |
Baseline characteristics
| Characteristic | Total | Sequence Group A | Sequence Group B |
|---|---|---|---|
| Age Continuous | 29.21 years STANDARD_DEVIATION 9.33 | 30.14 years STANDARD_DEVIATION 10.37 | 28.29 years STANDARD_DEVIATION 8.9 |
| Sex: Female, Male Female | 4 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Male | 10 Participants | 6 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 2 / — | 4 / — |
| serious Total, serious adverse events | 0 / 7 | 0 / 7 |
Outcome results
Primary
Area Under the Concentration-time Curve (AUC) of Desvenlafaxine After Single Dose of DVS SR by Metabolizer Status
AUC is drug level over time and measures drug metabolism. Variations in drug metabolism among individuals can be due to differences in genetic expression (phenotype) of Cytochrome P450 (CYP450) enzymes. Enzyme CYP2D6 has 4 metabolizer phenotypes: poor (PM), intermediate (IM), extensive (EM), ultrarapid (UM) metabolizers.
Time frame: single dose
Population: All participants from sequence groups A and B who received a single dose of venlafaxine ER.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Extensive Metabolizers (EM) | Area Under the Concentration-time Curve (AUC) of Desvenlafaxine After Single Dose of DVS SR by Metabolizer Status | 2701.79 ng*h/mL (90% CI) | 90% Confidence Interval 414.79 |
| Poor Metabolizers (PM) | Area Under the Concentration-time Curve (AUC) of Desvenlafaxine After Single Dose of DVS SR by Metabolizer Status | 3111.25 ng*h/mL (90% CI) | 90% Confidence Interval 1050.76 |
p-value: 0.427ANOVA
Primary
Area Under the Concentration-time Curve (AUC) of Desvenlafaxine After Single Dose of VEN ER by Metabolizer Status
AUC is drug level over time and measures drug metabolism. Variations in drug metabolism among individuals can be due to differences in genetic expression (phenotype) of Cytochrome P450 (CYP450) enzymes. Enzyme CYP2D6 has 4 metabolizer phenotypes: poor (PM), intermediate (IM), extensive (EM), ultrarapid (UM) metabolizers.
Time frame: single dose
Population: All participants from sequence groups A and B who received a single dose of venlafaxine ER.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Extensive Metabolizers (EM) | Area Under the Concentration-time Curve (AUC) of Desvenlafaxine After Single Dose of VEN ER by Metabolizer Status | 2703.50 ng*h/mL (90% CI) | 90% Confidence Interval 540.96 |
| Poor Metabolizers (PM) | Area Under the Concentration-time Curve (AUC) of Desvenlafaxine After Single Dose of VEN ER by Metabolizer Status | 436.14 ng*h/mL (90% CI) | 90% Confidence Interval 442.86 |
p-value: 0.018ANOVA
Primary
Area Under the Concentration-time Curve (AUC) of Venlafaxine After Single Dose of VEN ER by Metabolizer Status
AUC is drug level over time and measures drug metabolism. Variations in drug metabolism among individuals can be due to differences in genetic expression (phenotype) of Cytochrome P450 (CYP450) enzymes. Enzyme CYP2D6 has 4 metabolizer phenotypes: poor (PM), intermediate (IM), extensive (EM), ultrarapid (UM) metabolizers.
Time frame: single dose
Population: All participants from sequence groups A and B who received a single dose of venlafaxine ER.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Extensive Metabolizers (EM) | Area Under the Concentration-time Curve (AUC) of Venlafaxine After Single Dose of VEN ER by Metabolizer Status | 389.68 ng*h/mL (90% CI) | 90% Confidence Interval 462.45 |
| Poor Metabolizers (PM) | Area Under the Concentration-time Curve (AUC) of Venlafaxine After Single Dose of VEN ER by Metabolizer Status | 2328.41 ng*h/mL (90% CI) | 90% Confidence Interval 3460.47 |
p-value: <0.001ANOVA
Primary
Maximum Concentration (Cmax) of Desvenlafaxine After Single Dose of Desvenlafaxine Succinate Sustained-Release (DVS SR) by Metabolizer Status
Cmax is a measure of drug metabolism and is presented as least squares geometric mean with 90% Confidence Interval.Variations in drug metabolism among individuals can be due to differences in genetic expression (phenotype) of Cytochrome P450 (CYP450) enzymes. Enzyme CYP2D6 has 4 metabolizer phenotypes: poor (PM), intermediate (IM), extensive (EM), and ultrarapid (UM) metabolizers.
Time frame: single dose
Population: All participants from sequence groups A and B who received a single dose of venlafaxine ER.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Extensive Metabolizers (EM) | Maximum Concentration (Cmax) of Desvenlafaxine After Single Dose of Desvenlafaxine Succinate Sustained-Release (DVS SR) by Metabolizer Status | 102.22 ng/mL (90% CI) | 90% Confidence Interval 15.35 |
| Poor Metabolizers (PM) | Maximum Concentration (Cmax) of Desvenlafaxine After Single Dose of Desvenlafaxine Succinate Sustained-Release (DVS SR) by Metabolizer Status | 125.32 ng/mL (90% CI) | 90% Confidence Interval 28.34 |
p-value: 0.081ANOVA
Primary
Maximum Concentration (Cmax) of Desvenlafaxine After Single Dose of VEN ER by Metabolizer Status
Cmax is a measure of drug metabolism. Variations in drug metabolism among individuals can be due to differences in genetic expression (phenotype) of Cytochrome P450 (CYP450) enzymes. Enzyme CYP2D6 has 4 metabolizer phenotypes: poor (PM), intermediate (IM), extensive (EM), and ultrarapid (UM) metabolizers.
Time frame: single dose
Population: All participants from sequence groups A and B who received a single dose of venlafaxine ER.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Extensive Metabolizers (EM) | Maximum Concentration (Cmax) of Desvenlafaxine After Single Dose of VEN ER by Metabolizer Status | 95.63 ng/mL (90% CI) | 90% Confidence Interval 27.4 |
| Poor Metabolizers (PM) | Maximum Concentration (Cmax) of Desvenlafaxine After Single Dose of VEN ER by Metabolizer Status | 15.73 ng/mL (90% CI) | 90% Confidence Interval 20.27 |
p-value: 0.004ANOVA
Primary
Maximum Concentration (Cmax) of Venlafaxine After Single Dose of Venlafaxine Extended-release (VEN ER) by Metabolizer Status
Cmax is a measure of drug metabolism and presented as least squares geometric mean with 90% Confidence Interval. Variations in drug metabolism among individuals can be due to differences in genetic expression (phenotype) of Cytochrome P450 (CYP450) enzymes. Enzyme CYP2D6 has 4 metabolizer phenotypes: poor (PM), intermediate (IM), extensive (EM), and ultrarapid (UM) metabolizers.
Time frame: single dose
Population: All participants from sequence groups A and B who received a single dose of venlafaxine ER.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Extensive Metabolizers (EM) | Maximum Concentration (Cmax) of Venlafaxine After Single Dose of Venlafaxine Extended-release (VEN ER) by Metabolizer Status | 26.16 ng/mL (90% CI) | 90% Confidence Interval 17.7 |
| Poor Metabolizers (PM) | Maximum Concentration (Cmax) of Venlafaxine After Single Dose of Venlafaxine Extended-release (VEN ER) by Metabolizer Status | 77.46 ng/mL (90% CI) | 90% Confidence Interval 32.36 |
p-value: <0.001ANOVA