Healthy
Conditions
Keywords
Healthy subjects
Brief summary
The objectives of this study were: * to compare the pharmacokinetic profiles of two prototype controlled-release (CR) trazodone hydrochloride (HCl) 300 mg tablets versus two reference products: Trittico® AC (2 x 150 mg CR tablets) and Desyrel® (3 x 100 mg IR (immediate-release) tablets) under fasting condition; * to assess the controlled release properties of the two prototype formulations; * to select a prototype formulation for further development; * to validate the blood sampling schedule for future pivotal pharmacokinetic studies; * to determine the appropriate sample size for pivotal studies based in the intra-subject variability.
Interventions
DRUGTrazodone HCl
The dosage of trazodone.HCl during this treatment phase was a single oral dose of 300 mg (one CR tablet) at 07:30 (after an overnight fast of at least 10 hours) on clinic days.
Sponsors
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
* Healthy male and female subjects 18 to 45 years of age (inclusive). * Body mass within 10% of the ideal mass in relation to height and age, according to the BMI. * Body mass not less than 70 kg. The normal total circulating blood volume in males and in females is about 71 mL/kg and 65 mL/kg of the body mass, respectively (Meyer, 1988). No subject will have more than 13% of estimated blood volume taken during the study (Standards for the Practice of Blood Transfusion in South Africa, 1999). * Findings within the range of clinical acceptability in medical history and physical examination, and laboratory results within the normal ranges for the relevant laboratory tests (unless the clinical investigator considers the deviation to be irrelevant for the purpose of the study). * Normal ECG and vital signs, or abnormalities which the clinical investigator does not consider a disqualification for participation in the study. * Willingness to undergo pre- and post-study physical examinations, and pre- and post study laboratory investigations. * Ability to comprehend and willingness to sign both statements of informed consent (for screening and phase-related procedures). * Non-smoker or past smoker who stopped smoking at least 3 months before entering the study. * For females, the following conditions are to be met: 1. has been surgically sterilized, or 2. is of childbearing potential, and all of the following conditions are met: 1. had a normal menstrual flow within 1 month before study entry, and 2. has a negative urine pregnancy test at screening. If this test is positive, the subject will be excluded from the study before receiving study medication. In the rare circumstance that a pregnancy is discovered after the subjects received the study drug, every attempt must be made to follow such subjects to term, and 3. must agree to use an accepted method of contraception (i.e., spermicide and barrier methods or spermicide and intrauterine contraceptive device). The subject must agree to continue with the same method throughout the study. Hormonal contraceptives will be allowed, with a stable dose for at least one month prior to the first intake of study medication.
Exclusion criteria
* Evidence of psychiatric disorder, antagonistic personality, poor motivation, emotional or intellectual problems likely to limit the validity of consent to participate in the study or limit 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 will not affect the outcome of the study in the opinion of the clinical investigator. Use of hormonal contraceptive agents by females is allowed. * Participation in another study with an experimental drug 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 with evidence to this effect. * A major illness during the 3 months before commencement of the screening period. * History of hypersensitivity to the study drug or any related drugs. * History of bronchial asthma. * History of epilepsy. * Relevant history or laboratory or clinical findings indicative of acute or chronic disease, likely to influence 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 rate of \> 100 beats per minute or \< 45 beats per minute during the screening period, either supine or standing. * Positive testing for HIV, hepatitis B surface antigen and/or Hepatitis C antibodies. * Positive urine screen for drugs of abuse. * A urine pregnancy test (ß-HCG) either positive or not performed or lactation. * Positive urine screen for tobacco use (SureStepTM Smoke Check Tests and One-Step Cotinine (COT) Tests). * History of marijuana, barbiturate, amphetamine or narcotic abuse within 12 months prior to study start. * Significant liver disease, defined as active hepatitis or elevated liver enzymes (e.g. aspartate aminotransferase, alanine aminotransferase) \>2 times the upper boundary of the normal range.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Bioequivalence Based on AUC(0-t) | 72 hours | AUC(0-t) = Area under the plasma concentration curve vs (versus) time data pairs, where t is the time of the last quantifiable concentration. Measured in nanogram x hours per milliliter (ng\*h/mL). |
| Bioequivalence Based on AUC(0-∞) | 72 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). |
| Bioequivalence Based on Cmax | 72 hours | Cmax = Maximum plasma concentration. Measured in nanogram per milliliter (ng/mL). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Apparent Terminal Half-life (t½.z) | 72 hours | Apparent terminal half-life (t½.z) of trazodone in hours |
| Time to the Maximum Concentration (Tmax) | 72 hours | — |
| Apparent First Order Terminal Rate Constant [λz] | 72 hours | Apparent First order terminal rate constant \[λz\] of trazodone in plasma expressed in 1/hours. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Entire Study Population Includes groups randomized to receive Trazodone Contramid® OAD (prototype 1) First, Trazodone Contramid® OAD (prototype 2) First, Triticco® First, and Desyrel® First. | 24 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| First Intervention Period | Adverse Event | 0 | 0 | 1 | 0 |
| First Washout Period | Withdrawal by Subject | 1 | 0 | 0 | 0 |
| Second Intervention Period | Adverse Event | 0 | 0 | 1 | 0 |
| Second Washout Period | Withdrawal by Subject | 0 | 0 | 1 | 0 |
| Third Washout Period | Adverse Event | 1 | 0 | 0 | 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 | 24.9 years STANDARD_DEVIATION 7.3 |
| Region of Enrollment South Africa | 24 participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 7 / 21 | 9 / 20 | 14 / 23 | 14 / 21 |
| serious Total, serious adverse events | 0 / 21 | 0 / 20 | 0 / 23 | 0 / 21 |
Outcome results
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: 72 hours
Population: The dataset for pharmacokinetic analysis comprised the 19 subjects who completed the study as per protocol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Trazodone Contramid® OAD (Prototype 1) | Bioequivalence Based on AUC(0-∞) | 35122 ng*h/mL | Standard Deviation 8655 |
| Trazodone Contramid® OAD (Prototype 2) | Bioequivalence Based on AUC(0-∞) | 33373 ng*h/mL | Standard Deviation 9299 |
| Triticco® | Bioequivalence Based on AUC(0-∞) | 34165 ng*h/mL | Standard Deviation 9105 |
| Desyrel® | Bioequivalence Based on AUC(0-∞) | 32485 ng*h/mL | Standard Deviation 7621 |
90% CI: [91.8, 114]
90% CI: [95.1, 118]
90% CI: [85.1, 106]
90% CI: [88.3, 110]
Primary
Bioequivalence Based on AUC(0-t)
AUC(0-t) = Area under the plasma concentration curve vs (versus) time data pairs, where t is the time of the last quantifiable concentration. Measured in nanogram x hours per milliliter (ng\*h/mL).
Time frame: 72 hours
Population: The dataset for pharmacokinetic analysis comprised the 19 subjects who completed the study as per protocol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Trazodone Contramid® OAD (Prototype 1) | Bioequivalence Based on AUC(0-t) | 33883 ng*h/mL | Standard Deviation 8069 |
| Trazodone Contramid® OAD (Prototype 2) | Bioequivalence Based on AUC(0-t) | 32445 ng*h/mL | Standard Deviation 8868 |
| Triticco® | Bioequivalence Based on AUC(0-t) | 32928 ng*h/mL | Standard Deviation 8313 |
| Desyrel® | Bioequivalence Based on AUC(0-t) | 31841 ng*h/mL | Standard Deviation 7398 |
90% CI: [91.8, 114]
90% CI: [93.9, 117]
90% CI: [85.5, 106]
90% CI: [87.7, 109]
Primary
Bioequivalence Based on Cmax
Cmax = Maximum plasma concentration. Measured in nanogram per milliliter (ng/mL).
Time frame: 72 hours
Population: The dataset for pharmacokinetic analysis comprised the 19 subjects who completed the study as per protocol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Trazodone Contramid® OAD (Prototype 1) | Bioequivalence Based on Cmax | 1260 ng/mL | Standard Deviation 402 |
| Trazodone Contramid® OAD (Prototype 2) | Bioequivalence Based on Cmax | 1475 ng/mL | Standard Deviation 489 |
| Triticco® | Bioequivalence Based on Cmax | 1688 ng/mL | Standard Deviation 442 |
| Desyrel® | Bioequivalence Based on Cmax | 2081 ng/mL | Standard Deviation 492 |
90% CI: [63.2, 85]
90% CI: [51.5, 69.4]
90% CI: [71.5, 96.4]
90% CI: [58.4, 78.5]
Secondary
Apparent First Order Terminal Rate Constant [λz]
Apparent First order terminal rate constant \[λz\] of trazodone in plasma expressed in 1/hours.
Time frame: 72 hours
Population: The dataset for pharmacokinetic analysis comprised the 19 subjects who completed the study as per protocol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Trazodone Contramid® OAD (Prototype 1) | Apparent First Order Terminal Rate Constant [λz] | 0.07 1/hours | Standard Deviation 0.02 |
| Trazodone Contramid® OAD (Prototype 2) | Apparent First Order Terminal Rate Constant [λz] | 0.07 1/hours | Standard Deviation 0.02 |
| Triticco® | Apparent First Order Terminal Rate Constant [λz] | 0.07 1/hours | Standard Deviation 0.02 |
| Desyrel® | Apparent First Order Terminal Rate Constant [λz] | 0.08 1/hours | Standard Deviation 0.02 |
Secondary
Apparent Terminal Half-life (t½.z)
Apparent terminal half-life (t½.z) of trazodone in hours
Time frame: 72 hours
Population: The dataset for pharmacokinetic analysis comprised the 19 subjects who completed the study as per protocol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Trazodone Contramid® OAD (Prototype 1) | Apparent Terminal Half-life (t½.z) | 11.2 Hours | Standard Deviation 3.92 |
| Trazodone Contramid® OAD (Prototype 2) | Apparent Terminal Half-life (t½.z) | 10.9 Hours | Standard Deviation 3.55 |
| Triticco® | Apparent Terminal Half-life (t½.z) | 10.6 Hours | Standard Deviation 3.25 |
| Desyrel® | Apparent Terminal Half-life (t½.z) | 9.77 Hours | Standard Deviation 2.49 |
Secondary
Time to the Maximum Concentration (Tmax)
Time frame: 72 hours
Population: The dataset for pharmacokinetic analysis comprised the 19 subjects who completed the study as per protocol.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trazodone Contramid® OAD (Prototype 1) | Time to the Maximum Concentration (Tmax) | 12.0 Hours |
| Trazodone Contramid® OAD (Prototype 2) | Time to the Maximum Concentration (Tmax) | 6.00 Hours |
| Triticco® | Time to the Maximum Concentration (Tmax) | 13.0 Hours |
| Desyrel® | Time to the Maximum Concentration (Tmax) | 8.50 Hours |