Comparative Bioavailability Study of Two Prototypes of Trazodone Controlled-release Products and Two Marketed Reference Products in Healthy Volunteers

A Randomized, Four-way Crossover Pilot Study to Compare the Relative Bioavailability of Two Prototype Once-a-day Trazodone Hydrochloride Products and Two Marketed Reference Products Following an Equivalent Daily Dose Administration Under Fasting Conditions in Healthy Volunteers

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.

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.