Single Dose Two-periods Crossover Bioequivalence Study of Darifenacin Tablets in Healthy Volunteers.

Single Dose, Two-period, Crossover, Fed Bioequivalence Study of Darifenacin Extended Release Oral Formulation (Darisec(R) 15 mg) vs. Enablex(R) 15 mg in Healthy Volunteers.

The present study was designed to assess the bioequivalence and pharmacokinetic profiling of a brand generic formulation of darifenacin [Darisec(R)]vs. the innovator [Enablex(R)]in healthy volunteers after a high fat breakfast.

The bioequivalence will be evaluated using:

• the Area Under the Curve (AUC) and,
• the peak plasma concentration (Cmax).

Safety will be evaluated recording:

• vital signs
• adverse events,
• laboratory analysis.
• EKG and chest XRays.

Bioequivalence will be claimed if the drugs comply with local regulatory requirement, eg.:

• mean AUCt/AUCr and 90% confidence interval within 0.80-1.25
• mean Cmaxt/Cmaxr and 90% confidence interval within 0.80-1.25.

Darifenacin is a muscarinic receptor antagonist drug used to treat overactive bladder. There is a new formulation of darifenacin extended release developed by an argentinian pharmaceutical company and, according to regional regulations, a bioequivalence study should be performed to put it in the market.

The purpose of this study is to evaluate the relative bioavailability and pharmacokinetic profiling of a brand generic formulation of darifenacin [Darisec(R) 15 mg] vs. the innovator [Enablex(R) 15 mg] in 24 healthy uruguayan volunteers after a high fat breakfast of 1000 calories (50% fat, 35% carbohydrates (sugar, flour, etc.) and 15& proteins) to establish their average bioequivalence.

The bioequivalence will be evaluated using outcome measures that will be described later.

The pharmacokinetic characteristics of the drugs will be described calculating:

• the time to Cmax (Tmax)
• the elimination constant (Ke),
• the elimination half-life (t1/2e)and,
• the systemic clearance (Cls.

Safety will be evaluated recording:

• vital signs (blood pressure, heart rate, body temperature)
• adverse events,
• laboratory analysis (hemogram, hepatic enzymes, creatinine, sugar in blood,etc.).
• EKG and chest XRays.

Bioequivalence will be claimed if the drugs comply with local and FDA regulatory requirement, eg.:

• mean AUCt/AUCr and 90% confidence interval within 0.80-1.25
• mean Cmaxt/Cmaxr and 90% confidence interval within 0.80-1.25.

Safety will be evaluated comparing incidences of adverse events/adverse effects for both products.

Inclusion Criteria:

• Healthy male or female subjects 18 to 50 years of age (inclusive)
• In good health, as determined by lack of clinically significant abnormalities at screening as judged by the physician.
• Female subjects are required to use a medically accepted method of hormonal contraception or abstinence throughout the entire study period and for one week after the study is completed.
• Body mass index within the range of 18.5 and 29.9 kg/m2 and weight at least 45 kg.

Exclusion Criteria:

• Known hypersensitivity or severe adverse event to darifenacin or similar drugs.
• Urinary retention, narrow-angle glucoma, myasthenia gravis, severe hepatic impairment, severe ulcerative colitis, toxic megacolon.
• Symptomatic hiatus hernia, erosive or symptomatic gastroesophageal reflux disease/heartburn (>2 days in a week), severe constipation, gastrointestinal obstructive disorder, and gastric retention.
• Clinically significant cardiac abnormalities, fainting, low blood pressure upon standing, irregular heartbeats.
• Acute or chronic bronchospastic disease (including asthma and Chronic Obstructive Pulmonary Disease).
• Clinically significant drug allergy or history of atopic allergy (asthma, urticaria, eczematous dermatitis).
• Smokers of more than 5 cigarettes a week.
• Regular use of any drugs known to induce or inhibit hepatic drug metabolism (particularly those that affect CYP2D6) within 30 days prior to each study drug administration.
• Any surgical or medical condition wich might significantly alter the absorption, distribution, metabolism or excretion of drugs which may jeopardize participation in the study.
• Immunodeficiency diseases, including a positive HIV (Elisa or Western blot) test result.
• Positive hepatitis B Surface antigen (HBsAg) or Hepatitis C test result.
• Drug or alcohol abuse within the 6 months prior to dosing.
• Use of prescription drugs within 1 month prior to dosing, or over-the-counter medication (vitamine, herbal supplements, dietary supplements) within 2 weeks prior to dosing. Paracetamol and ibuprofen are acceptable.
• Participation in any clinical investigation within 4 weeks prior to dosing.
• Donation or loss of 400 ml or more of blood within 2 months prior to dosing.
• significant illness within 2 weeks prior to dosing.
• Other protocol-defined inclusion/exclusion criteria may apply.