Healthy
Conditions
Keywords
bioavailability, pharmacokinetics, healthy, crossover, trazodone
Brief summary
The objective of the study is to compare the pharmacokinetic profiles of extended-release and immediate-release trazodone formulations
Detailed description
The bioavailability of once-daily trazodone extended-release 300 mg caplets (test product) and trazodone immediate-release 100 mg tablets administered q8h (reference product) will be compared in healthy adult volunteers in a randomized, crossover fashion. Morning doses will be administered after an overnight fast. Blood samples will be collected predose and at pre-defined times over 72 hours following the morning dose. Pharmacokinetic parameters will be analyzed using ANOVA. Comparative bioavailability will be assessed on the basis of the ratio of least-squares means and/or 90% confidence interval criteria.
Interventions
DRUGTrazodone HCl
100 mg immediate-release tablet, dosing q8h
Sponsors
Algorithme Pharma Inc
Labopharm Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Availability for entire study period and willingness to adhere to protocol requirements as evidenced by signed informed consent * Male or female volunteer, aged between 18 and 45 years inclusively * BMI ≥20 and \<30 kg/m2 * Minimum body weight: 60 kg * Clinical laboratory values within normal range, or without clinical significance * Healthy according to medical history, clinical laboratory results and physical examination * Nonsmoker or ex-smoker
Exclusion criteria
* Significant history of hypersensitivity to trazodone or any related products, or severe hypersensitivity reactions to any drugs * Presence or history of significant gastrointestinal, liver or kidney disease, or any other conditions known to interfere with the absorption, distribution, metabolism, or excretion of drugs or known to potentiate or predispose to undesired effects * Presence of significant cardiovascular, pulmonary, hematologic, neurological, psychiatric, endocrine, immunologic, or dermatologic disease * Suicidal tendency, history of or disposition to seizures, state of confusion, clinically relevant psychiatric disease * Use of MAO inhibitors within 28 days of day 1 of the study * Presence of significant heart disease or disorder according to ECG * Seated systolic blood pressure lower than 90 or over 140 mmHg or diastolic blood pressure lower than 50 or over 90 mmHg at screening * Maintenance therapy with any drug, or significant history of drug dependency or alcohol abuse (\>3 units of alcohol per day, intake of excessive alcohol, acute or chronic) * Any clinically significant illness in the previous 28 days before day 1 of this study * Use of any enzyme-modifying drugs, including strong inhibitors of cytochrome P450 (CYP) enzymes (such as cimetidine, fluoxetine, quinidine, erythromycin, ciprofloxacin, fluconazole, ketoconazole, diltiazem, and HIV antivirals) and strong inducers of CYP enzymes (such as barbiturates, carbamazepine, glucocorticoids, phenytoin, and rifampin), in the previous 28 days before day 1 of this study * Females who are pregnant according to a positive serum pregnancy test, or are lactating * Females of childbearing potential who refuse to use an acceptable method of contraception from the screening visit and throughout the study * Volunteers who took an investigational product (in another clinical trial) or donated 50 mL or more of blood in the previous 28 days before day 1 of this study * Poor motivation, intellectual problems likely to limit the validity of consent to participate in the study or limit the ability to comply with the protocol requirements or inability to cooperate adequately, inability to understand and to observe the instructions of the physician * Donation of 500 mL or more of blood (Canadian Blood Services, Hema-Quebec, clinical studies, etc) in the previous 56 days before day 1 of the study * Positive urine screening for drugs of abuse * Any history of tuberculosis and/or prophylaxis for tuberculosis * Positive results to HIV, HBsAg, or anti-HCV tests
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Bioequivalence Based on Cmax | 72 hours post-dose | Cmax = Maximum plasma concentration Measured in nanograms per millilitre (ng/mL) |
| Bioequivalence Based on AUCT | 72 hours post-dose | AUCT = Area under the concentration-time curve from 0 to the time of the last quantifiable concentration |
| Bioequivalence Based on AUC∞ | 72 hours post-dose | AUC∞ = Area under the concentration-time curve extrapolated to infinity |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time of Maximum Measured Plasma Concentration (Tmax) | 72 hours post-dose | — |
| Apparent Terminal Elimination Half-Life [T½el] | 72 hours post-dose | The elimination half-life (T½el) of trazodone in plasma (time it takes for the concentration of trazodone to fall to half), expressed in hours. |
| Area Under the Concentration-time Curve From 0 to 24 Hours [AUC0-24] | 24 hours | — |
Countries
Canada
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Entire Study Population Includes groups randomized to receive Test first and Reference first. | 24 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention Period | Adverse Event | 1 | 1 |
| First Intervention Period | Withdrawal by Subject | 1 | 0 |
| Second Intervention Period | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Entire Study Population |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 24 Participants |
| Age Continuous | 35 years STANDARD_DEVIATION 6 |
| Region of Enrollment Canada | 24 participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 20 / 23 | 21 / 22 |
| serious Total, serious adverse events | 0 / 23 | 0 / 22 |
Outcome results
Primary
Bioequivalence Based on AUC∞
AUC∞ = Area under the concentration-time curve extrapolated to infinity
Time frame: 72 hours post-dose
Population: The dataset for pharmacokinetic analysis comprised the 20 subjects who completed both study periods.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Trazodone Contramid® OAD | Bioequivalence Based on AUC∞ | 30913.7 ng*h/mL | Standard Deviation 11904.8 |
| Desyrel® | Bioequivalence Based on AUC∞ | 37273.4 ng*h/mL | Standard Deviation 10738.5 |
90% CI: [70.67, 90.68]
Primary
Bioequivalence Based on AUCT
AUCT = Area under the concentration-time curve from 0 to the time of the last quantifiable concentration
Time frame: 72 hours post-dose
Population: The dataset for pharmacokinetic analysis comprised the 20 subjects who completed both study periods.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Trazodone Contramid® OAD | Bioequivalence Based on AUCT | 29180.6 ng*h/mL | Standard Deviation 10557.1 |
| Desyrel® | Bioequivalence Based on AUCT | 36002.4 ng*h/mL | Standard Deviation 9636.4 |
90% CI: [69.7, 88.51]
Primary
Bioequivalence Based on Cmax
Cmax = Maximum plasma concentration Measured in nanograms per millilitre (ng/mL)
Time frame: 72 hours post-dose
Population: The dataset for pharmacokinetic analysis comprised the 20 subjects who completed both study periods.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Trazodone Contramid® OAD | Bioequivalence Based on Cmax | 1060.8 ng/mL | Standard Deviation 366.6 |
| Desyrel® | Bioequivalence Based on Cmax | 1743.3 ng/mL | Standard Deviation 470.1 |
90% CI: [50.99, 69.81]
Secondary
Apparent Terminal Elimination Half-Life [T½el]
The elimination half-life (T½el) of trazodone in plasma (time it takes for the concentration of trazodone to fall to half), expressed in hours.
Time frame: 72 hours post-dose
Population: The dataset for pharmacokinetic analysis comprised the 20 subjects who completed both study periods.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Trazodone Contramid® OAD | Apparent Terminal Elimination Half-Life [T½el] | 14.37 Hours | Standard Deviation 4.31 |
| Desyrel® | Apparent Terminal Elimination Half-Life [T½el] | 12.16 Hours | Standard Deviation 3.51 |
Secondary
Area Under the Concentration-time Curve From 0 to 24 Hours [AUC0-24]
Time frame: 24 hours
Population: The dataset for pharmacokinetic analysis comprised the 20 subjects who completed both study periods.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Trazodone Contramid® OAD | Area Under the Concentration-time Curve From 0 to 24 Hours [AUC0-24] | 16885.8 ng*h/mL | Standard Deviation 5453 |
| Desyrel® | Area Under the Concentration-time Curve From 0 to 24 Hours [AUC0-24] | 22512.8 ng*h/mL | Standard Deviation 5045.2 |
Secondary
Time of Maximum Measured Plasma Concentration (Tmax)
Time frame: 72 hours post-dose
Population: The dataset for pharmacokinetic analysis comprised the 20 subjects who completed both study periods.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trazodone Contramid® OAD | Time of Maximum Measured Plasma Concentration (Tmax) | 6.00 hours |
| Desyrel® | Time of Maximum Measured Plasma Concentration (Tmax) | 9.50 hours |