A Study to Compare the Bioavailability of 300 mg Trazodone Hydrochloride Extended-release Caplets and 100 mg Trazodone Hydrochloride Immediate-release Tablets at Steady State

Study Overview
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Brief Summary
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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.

Official Title
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A Randomized, Two-way Crossover Study to Compare the Bioavailability of 300 mg Trazodone Hydrochloride Extended-release Caplets (Containing Contramid®) (Administered Once Daily) and 100 mg Trazodone Hydrochloride Immediate-release Tablets (Administered Three Times Daily) at Steady State

Conditions
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Healthy Subjects, Bioavailability, Pharmacokinetics

Intervention / Treatment
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* Drug: Trazodone HCl
* Drug: Trazodone HCl


Participation Criteria
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Eligibility Criteria
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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: had been surgically sterilized or undergone a hysterectomy, or was of childbearing potential, and all of the following conditions were met: 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. 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. 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Trazodone HCl OAD<br>OAD: Once A Day | Drug: Trazodone HCl<br>* 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.<br>* Other names: Oleptro;|
| Active Comparator: Trazodone HCl (Apotex Corp.)<br> | Drug: Trazodone HCl<br>* Dosage form: Immediate-release tablet containing 100 mg trazodone HCl Dose regimen: 100 mg trazodone HCl (one immediate-release tablet) once (at 23:30) on Days 1 and 11, 100 mg trazodone HCl (one immediate-release tablet) twice (at 23:30 and 11:30) on Days 2 and 10, 100 mg trazodone HCl (one immediate-release tablet) three times daily (at 23:30, 07:30 and 15:30) on Days 3 to 9. Evening doses were administered after a fast of at least 4 hours.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bioequivalence Based on Cmax,ss | Cmax,ss = Maximum plasma concentration (Cmax) at steady state (ss): (Cmax,ss). Measured in nanograms per milliliter (ng/mL). | 9 days | 
| 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). | 9 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Minimum Plasma Concentration (Cmin,ss) | Minimum plasma concentration at steady state (Cmin,ss). Measured in nanograms per milliliter (ng/mL) | 9 days | 
| Plasma Concentration at 24 Hours Post-evening Dose (C24h) | Plasma concentration at 24 hours post-evening dose (C24h) in nanograms per milliliter (ng/mL) | 9 days | 
| Time to Peak Exposure (Tmax) | Time to peak exposure (Tmax) at steady state. | 9 days | 
| 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. | 9 days | 
| 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 | 9 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Healthy subjects, Bioavailability, Pharmacokinetics, Trazodone, Steady-state