Comparative Bioavailability Study of Two Prototypes of Trazodone Controlled-release Products and Two Marketed Reference Products in Healthy Volunteers
Condition: Healthy
Intervention: Trazodone HCl; Trazodone HCl; Trazodone HCl; Trazodone HCl
Intervention description: 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.; 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.; The dosage of trazodone.HCl during this treatment phase was 2 oral doses of 150 mg each: one controlled-release (CR) tablet at 07:30 (after an overnight fast of at least 10 hours) and 19:30 (after a fast of at least 2 hours) on clinic days.; The dosage of trazodone.HCl during this treatment phase was three oral doses of 100 mg each: one immediate-release (IR) tablet at 07:30 (after an overnight fast of at least 10 hours), 15:30 and 23:30 (both dosages after a fast of at least 2 hours) on clinic days.
Intervention MeSH terms: Trazodone
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Enrollment: 24.0
Sex: All
Minimum age: 18 Years
Maximum age: 45 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Healthy subjects

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.
    

Eligibility criteria:

        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.