Bioavailability, Healthy Subjects, Pharmacokinetics
Conditions
Keywords
Healthy subjects, Bioavailability, Pharmacokinetics, Trazodone, Steady-state
Brief summary
The purpose of this study was to compare the pharmacokinetic profiles at steady state of the test product, 300 mg trazodone hydrochloride (HCl) extended-release caplets (containing Contramid®), when administered once daily, and the reference product, 100 mg trazodone HCl immediate-release tablets (Apotex Corp.), when administered three times daily, for one week. For this purpose, the rate and extent of absorption of trazodone and formation of m-chlorophenylpiperazine (mCPP) after administration of multiple doses of up to 300 mg of each of the two formulations was compared.
Interventions
DRUGTrazodone HCl
Dosage form: Extended-release caplets containing 300 mg trazodone HCl and extended-release caplets containing 150 mg trazodone HCl (the 150 mg dosage form was only used for the up and down titration, and was not evaluated in the study). Dose regimen: 75 mg trazodone HCl (½ x 150 mg extended-release caplet) on Days 1 and 11, 150 mg trazodone HCl (one extended-release caplet) on Days 2 and 10, 300 mg trazodone HCl (one extended-release caplet) on Days 3 to 9, each at 23:30 after a fast 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 ideal mass in relation to height and age, according to Body Mass Index. * Body mass not less than 60 kg. * Findings within the range of clinical acceptability in medical history and physical examination, and laboratory results within the reference ranges for the relevant laboratory tests (unless the investigator considered the deviation to be irrelevant for the purpose of the study). * Normal electrocardiogram (ECG) and vital signs, or abnormalities which the investigator did not consider a disqualification for participation in the study. * Willingness to undergo pre- and post-study physical examinations and 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 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 circumstance that a pregnancy was discovered after the subjects received the study medication, every attempt had 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 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 would not affect the outcome of the study in the opinion of the investigator. * 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 with evidence to this effect. * 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 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 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 on Cmax,ss | 9 days | Cmax,ss = Maximum plasma concentration (Cmax) at steady state (ss): (Cmax,ss). Measured in nanograms per milliliter (ng/mL). |
| Bioequivalence Based on AUCss | 9 days | AUCss = Area under the plasma concentration curve (AUC) vs. time data pairs at steady state (ss): AUCss. Measured in nanograms x hours per milliliter (ng\*h/mL). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Peak Exposure (Tmax) | 9 days | Time to peak exposure (Tmax) at steady state. |
| Minimum Plasma Concentration (Cmin,ss) | 9 days | Minimum plasma concentration at steady state (Cmin,ss). Measured in nanograms per milliliter (ng/mL) |
| Percentage Peak-Trough Fluctuation (%PTF) | 9 days | Percentage Peak-Trough Fluctuation (%PTF) of trazodone calculated as \[100\*(Cmax-Cmin)/Cav\]. Cmax: Maximum plasma concentration Cmin: Minimum plasma concentration Cav: Average plasma concentration |
| Percentage Swing | 9 days | Percentage swing is a pharmacokinetic parameter calculated as follows: ((Cmax,ss - Cmin,ss)/Cmin,ss)\*100. Where: Cmax,ss = Maximum concentration at steady state; Cmin,ss = Minimum concentration at steady state. It was calculated over 24 hours on day 9. |
| Plasma Concentration at 24 Hours Post-evening Dose (C24h) | 9 days | Plasma concentration at 24 hours post-evening dose (C24h) in nanograms per milliliter (ng/mL) |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Entire Study Population Includes groups randomized to receive Trazodone Contramid® OAD (Once-A-Day) test product first and Trazodone IR (Apotex Corp.) reference product first.
IR = Immediate Release | 30 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention Period | Adverse Event | 1 | 0 |
| Washout Period | Adverse Event | 0 | 1 |
| Washout Period | Positive pregnancy test | 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 | 30 Participants |
| Age Continuous | 25.7 years STANDARD_DEVIATION 8.4 |
| Region of Enrollment South Africa | 30 participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 11 / 28 | 13 / 29 |
| serious Total, serious adverse events | 0 / 28 | 0 / 29 |
Outcome results
Primary
Bioequivalence Based on AUCss
AUCss = Area under the plasma concentration curve (AUC) vs. time data pairs at steady state (ss): AUCss. Measured in nanograms x hours per milliliter (ng\*h/mL).
Time frame: 9 days
Population: The dataset for pharmacokinetic analysis comprised the 27 subjects who completed the study as per protocol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Trazodone Contramid® OAD | Bioequivalence Based on AUCss | 29131.374 ng*h/mL | Standard Deviation 9930.767 |
| Trazodone HCl (Apotex Corp.) | Bioequivalence Based on AUCss | 33058.024 ng*h/mL | Standard Deviation 8006.118 |
90% CI: [81.05, 90.67]
Primary
Bioequivalence Based on Cmax,ss
Cmax,ss = Maximum plasma concentration (Cmax) at steady state (ss): (Cmax,ss). Measured in nanograms per milliliter (ng/mL).
Time frame: 9 days
Population: The dataset for pharmacokinetic analysis comprised the 27 subjects who completed the study as per protocol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Trazodone Contramid® OAD | Bioequivalence Based on Cmax,ss | 1812.026 ng/mL | Standard Deviation 620.625 |
| Trazodone HCl (Apotex Corp.) | Bioequivalence Based on Cmax,ss | 3117.778 ng/mL | Standard Deviation 757.508 |
90% CI: [49.99, 63.94]
Secondary
Minimum Plasma Concentration (Cmin,ss)
Minimum plasma concentration at steady state (Cmin,ss). Measured in nanograms per milliliter (ng/mL)
Time frame: 9 days
Population: The dataset for pharmacokinetic analysis comprised the 27 subjects who completed the study as per protocol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Trazodone Contramid® OAD | Minimum Plasma Concentration (Cmin,ss) | 673.889 ng/mL | Standard Deviation 354.647 |
| Trazodone HCl (Apotex Corp.) | Minimum Plasma Concentration (Cmin,ss) | 842.763 ng/mL | Standard Deviation 273.592 |
Secondary
Percentage Peak-Trough Fluctuation (%PTF)
Percentage Peak-Trough Fluctuation (%PTF) of trazodone calculated as \[100\*(Cmax-Cmin)/Cav\]. Cmax: Maximum plasma concentration Cmin: Minimum plasma concentration Cav: Average plasma concentration
Time frame: 9 days
Population: The dataset for pharmacokinetic analysis comprised the 27 subjects who completed the study as per protocol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Trazodone Contramid® OAD | Percentage Peak-Trough Fluctuation (%PTF) | 97.090 Percentage Peak-Trough Fluctuation | Standard Deviation 28.357 |
| Trazodone HCl (Apotex Corp.) | Percentage Peak-Trough Fluctuation (%PTF) | 174.768 Percentage Peak-Trough Fluctuation | Standard Deviation 69.648 |
Secondary
Percentage Swing
Percentage swing is a pharmacokinetic parameter calculated as follows: ((Cmax,ss - Cmin,ss)/Cmin,ss)\*100. Where: Cmax,ss = Maximum concentration at steady state; Cmin,ss = Minimum concentration at steady state. It was calculated over 24 hours on day 9.
Time frame: 9 days
Population: The dataset for pharmacokinetic analysis comprised the 27 subjects who completed the study as per protocol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Trazodone Contramid® OAD | Percentage Swing | 210.769 Percentage swing | Standard Deviation 127.806 |
| Trazodone HCl (Apotex Corp.) | Percentage Swing | 302.805 Percentage swing | Standard Deviation 144.467 |
Secondary
Plasma Concentration at 24 Hours Post-evening Dose (C24h)
Plasma concentration at 24 hours post-evening dose (C24h) in nanograms per milliliter (ng/mL)
Time frame: 9 days
Population: The dataset for pharmacokinetic analysis comprised the 27 subjects who completed the study as per protocol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Trazodone Contramid® OAD | Plasma Concentration at 24 Hours Post-evening Dose (C24h) | 747.270 ng/mL | Standard Deviation 329.025 |
| Trazodone HCl (Apotex Corp.) | Plasma Concentration at 24 Hours Post-evening Dose (C24h) | 919.111 ng/mL | Standard Deviation 289.382 |
Secondary
Time to Peak Exposure (Tmax)
Time to peak exposure (Tmax) at steady state.
Time frame: 9 days
Population: The dataset for pharmacokinetic analysis comprised the 27 subjects who completed the study as per protocol.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trazodone Contramid® OAD | Time to Peak Exposure (Tmax) | 8.00 hours |
| Trazodone HCl (Apotex Corp.) | Time to Peak Exposure (Tmax) | 8.33 hours |