Healthy
Conditions
Keywords
Healthy subjects
Brief summary
The objective of this study was to compare the pharmacokinetic profiles of the test product, 300 mg trazodone hydrochloride (HCl) extended-release caplets (containing Contramid®), when administered as a single dose, and the reference product, 100 mg trazodone HCl immediate-release tablets (Apotex Corp), when administered three times daily. For this purpose the rate and extent of absorption of trazodone and formation of m-chlorophenylpiperazine (mCPP) after administration of the two formulations, were compared under fasting conditions.
Interventions
DRUGTrazodone HCl
Dosage form: Extended-release caplets containing 300 mg trazodone HCl Dose: 300 mg trazodone HCl extended-release caplets (one caplet) at 23:30 on Day 1 of the test product treatment period following a fasting period of at least 4 hours.
Sponsors
Labopharm Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy male and female subjects 18 to \< 56 years of age. * Body mass within 10% of the ideal mass in relation to height and age, according to Body Mass Index. * Body mass not less than 53 kg. * Findings within the range of clinical acceptability in medical history and physical examination, and laboratory results within the laboratory reference ranges for the relevant laboratory tests (unless the investigator considered the deviation to be irrelevant for the purpose of the study). * Normal 12-lead electrocardiogram (ECG) and vital signs, or abnormalities, which the investigator did not consider a disqualification for participation in the study. * Willingness to undergo a pre- and post-study physical examination and laboratory investigations. * Ability to comprehend and willingness to sign both statements of informed consent (for screening and period-related procedures). * Non-smoker or past smoker who stopped the use of any form of tobacco, including snuff or similar products, at least 3 months before entering the study. * For females, the following conditions had to be met: 1. Had been surgically sterilized or undergone a hysterectomy, or 2. Was of childbearing potential, and all of the following conditions were met: 1. Had a negative pregnancy test at screening. If this test was positive, the subject was to be excluded from the study before receiving study medication. In the rare circumstance that a pregnancy was discovered after the subjects received the study medication, every attempt was to be made to follow such subjects to term. 2. Had to agree to use an accepted method of contraception (i.e., spermicide and barrier methods or spermicide and non-hormonal intrauterine contraceptive device). The subject had to agree to continue with the same method throughout the study. Hormonal contraceptives were not allowed. 3. Females not of childbearing potential could also have been included if they had no menstrual period for one year and were considered as post-menopausal.
Exclusion criteria
* Evidence of psychiatric disorder, antagonistic personality, poor motivation, emotional or intellectual problems likely to have limited the validity of consent to participate in the study or to have limited the ability to comply with protocol requirements. * History of, or current compulsive alcohol abuse (\> 10 drinks weekly), or regular exposure to other substances of abuse. * Use of any medication, prescribed or over-the-counter, within 2 weeks prior to the first administration of study medication except if this would not have affected the outcome of the study in the opinion of the investigator. Hormonal contraceptive agents were not allowed. * Participation in another study with an experimental drug, where the last administration (of previous study medication) was within 8 weeks before the first administration of study medication. * Treatment within the previous 3 months with any drug with a well-defined potential for adversely affecting a major organ or system. * A major illness during the 3 months before commencement of the screening period. * History of hypersensitivity to the study medication or any related medication. * History of bronchial asthma. * History of epilepsy. * History of porphyria. * Relevant history or laboratory or clinical findings indicative of acute or chronic disease, likely to have influenced the study outcome. * Donation or loss of blood equal to or exceeding 500 mL during the 8 weeks before the first administration of study medication. * Diagnosis of hypotension made during the screening period. * Diagnosis of hypertension made during the screening period or current diagnosis of hypertension. * Resting pulse of \> 100 beats per minute or \< 40 beats per minute during the screening period, either supine or standing. * Positive testing for HIV and/or Hepatitis B and/or Hepatitis C. * Positive urine screen for drugs of abuse. * Positive urine screen for tobacco use. * A serum pregnancy test (beta human chorionic gonadotropin \[β-HCG\]) either positive or not performed or lactation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Bioequivalence Based Cmax | 68 hours | Cmax = Maximum plasma concentration. Measured in nanogram per milliliter (ng/mL). |
| Bioequivalence Based on AUC(0-tlast) | 68 hours | AUC(0-tlast) = Area under the plasma concentration curve (AUC) vs (versus) time data pairs, where tlast is the time of the last quantifiable concentration. Measured in nanogram x hours per milliliter (ng\*h/mL). |
| Bioequivalence Based on AUC(0-∞) | 68 hours | AUC(0-∞) = Area under the plasma concentration curve vs time data pairs, with extrapolation to infinity (∞). Measured in nanogram x hours per milliliter (ng\*h/mL). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Maximum Plasma Concentration (Tmax) | 68 hours | — |
| Apparent Terminal Half-life (t½.z) | 68 hours | The elimination half-life (T½z) of trazodone in plasma (time it takes for the concentration of trazodone to fall to half), expressed in hours. |
| Area Under the Plasma Concentration vs. Time Data Pairs, for the First 24 Hours [AUC(0-24)] | 24 hours | — |
| Apparent Terminal Elimination Rate Constant (λz) | 68 hours | The elimination rate constant of trazodone (Lamda z). It is the ratio of clearance to volume of distribution and is expressed in units of 1/hour. This constant is used in half-life calculations. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Entire Study Population Includes groups randomized to receive Test first and Reference first. | 26 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention Period | Adverse Event | 1 | 1 |
| Washout Period of 7 Days | Withdrawal by Subject | 0 | 1 |
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 | 26 Participants |
| Age Continuous | 25.2 years STANDARD_DEVIATION 10.88 |
| Region of Enrollment South Africa | 26 participants |
| Sex: Female, Male Female | 16 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 | 7 / 24 | 8 / 25 |
| serious Total, serious adverse events | 0 / 24 | 0 / 25 |
Outcome results
Primary
Bioequivalence Based Cmax
Cmax = Maximum plasma concentration. Measured in nanogram per milliliter (ng/mL).
Time frame: 68 hours
Population: The dataset for pharmacokinetic analysis comprised the 23 subjects who completed the study as per protocol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Trazodone Contramid® OAD | Bioequivalence Based Cmax | 1230.7 ng/mL | Standard Deviation 499.1 |
| Trazodone IR (Apotex Corp.) | Bioequivalence Based Cmax | 2947.7 ng/mL | Standard Deviation 734.7 |
90% CI: [34.4, 46]
Primary
Bioequivalence Based on AUC(0-∞)
AUC(0-∞) = Area under the plasma concentration curve vs time data pairs, with extrapolation to infinity (∞). Measured in nanogram x hours per milliliter (ng\*h/mL).
Time frame: 68 hours
Population: The dataset for pharmacokinetic analysis comprised the 23 subjects who completed the study as per protocol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Trazodone Contramid® OAD | Bioequivalence Based on AUC(0-∞) | 29672.5 h*ng/mL | Standard Deviation 8373.8 |
| Trazodone IR (Apotex Corp.) | Bioequivalence Based on AUC(0-∞) | 35258.5 h*ng/mL | Standard Deviation 10067.4 |
90% CI: [76.5, 91.1]
Primary
Bioequivalence Based on AUC(0-tlast)
AUC(0-tlast) = Area under the plasma concentration curve (AUC) vs (versus) time data pairs, where tlast is the time of the last quantifiable concentration. Measured in nanogram x hours per milliliter (ng\*h/mL).
Time frame: 68 hours
Population: The dataset for pharmacokinetic analysis comprised the 23 subjects who completed the study as per protocol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Trazodone Contramid® OAD | Bioequivalence Based on AUC(0-tlast) | 28138.4 hr*ng/mL | Standard Deviation 8400 |
| Trazodone IR (Apotex Corp.) | Bioequivalence Based on AUC(0-tlast) | 34272.4 hr*ng/mL | Standard Deviation 9792.8 |
90% CI: [74.2, 88.3]
Secondary
Apparent Terminal Elimination Rate Constant (λz)
The elimination rate constant of trazodone (Lamda z). It is the ratio of clearance to volume of distribution and is expressed in units of 1/hour. This constant is used in half-life calculations.
Time frame: 68 hours
Population: The dataset for pharmacokinetic analysis comprised the 23 subjects who completed the study as per protocol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Trazodone Contramid® OAD | Apparent Terminal Elimination Rate Constant (λz) | 0.064 1/hour | Standard Deviation 0.018 |
| Trazodone IR (Apotex Corp.) | Apparent Terminal Elimination Rate Constant (λz) | 0.090 1/hour | Standard Deviation 0.024 |
Secondary
Apparent Terminal Half-life (t½.z)
The elimination half-life (T½z) of trazodone in plasma (time it takes for the concentration of trazodone to fall to half), expressed in hours.
Time frame: 68 hours
Population: The dataset for pharmacokinetic analysis comprised the 23 subjects who completed the study as per protocol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Trazodone Contramid® OAD | Apparent Terminal Half-life (t½.z) | 11.8 Hours | Standard Deviation 3.7 |
| Trazodone IR (Apotex Corp.) | Apparent Terminal Half-life (t½.z) | 8.3 Hours | Standard Deviation 2.5 |
Secondary
Area Under the Plasma Concentration vs. Time Data Pairs, for the First 24 Hours [AUC(0-24)]
Time frame: 24 hours
Population: The dataset for pharmacokinetic analysis comprised the 23 subjects who completed the study as per protocol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Trazodone Contramid® OAD | Area Under the Plasma Concentration vs. Time Data Pairs, for the First 24 Hours [AUC(0-24)] | 18331.0 h*ng/mL | Standard Deviation 4966.4 |
| Trazodone IR (Apotex Corp.) | Area Under the Plasma Concentration vs. Time Data Pairs, for the First 24 Hours [AUC(0-24)] | 24602.2 h*ng/mL | Standard Deviation 6097.5 |
Secondary
Time to Maximum Plasma Concentration (Tmax)
Time frame: 68 hours
Population: The dataset for pharmacokinetic analysis comprised the 23 subjects who completed the study as per protocol.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Trazodone Contramid® OAD | Time to Maximum Plasma Concentration (Tmax) | 9.00 Hours | Full Range 3.64 |
| Trazodone IR (Apotex Corp.) | Time to Maximum Plasma Concentration (Tmax) | 8.33 Hours | Full Range 1.66 |