Single Dose Bioequivalence Study of Darifenacin Tablets 7.5 mg in Fed Healthy Volunteers.

Comparative Bioavailability of Darifenacin Extended Release Oral Formulation [Darisec(R)7.5 mg vs. Enablex(R)7.5 mg]: Single-dose, Postprandial State, Randomized, Two-sequence, Two-period, Crossover Study in Healthy Volunteers.

The proposed study was designed as a randomized two-sequence, two period crossover trial to assess the bioequivalence, pharmacokinetic profiling and safety of a brand generic formulation of darifenacin [Darisec(R) 7.5 mg] vs. the innovator [Enablex(R)7.5 mg]in healthy volunteers in postprandial state.

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. A bioequivalence study will be performed to validate pharmaceutical development before introducing the product in the market.

The purpose in this study is to evaluate the relative bioavailability, pharmacokinetic profiling and safety of a brand generic formulation of darifenacin [Darisec(R) 7.5 mg] vs. the innovator [Enablex(R) 7.5 mg]in 24 healthy uruguayan volunteers after a high fat breakfast of 1000 calories (50% fat, 35% carbohydrates, and 15% proteins)to establish their average bioequivalence.

The bioequivalence will be evaluated using:

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

The pharmacokinetic characteristics of the drug formulations will be described calculating:

• The time to peak concentration (Tmax)
• The elimination constant (Ke)
• The elimination half-life (t1/2e)
• The systemic clearance (Cls)

Safety will be evaluated recording:

• Reported adverse events
• Vital signs (blood pressure, heart rate, body temperature)
• 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 requirements:

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

Pharmacokinetic profiling will be evaluated by describing the pharmacokinetic characteristics of both drug in adequate two-way tables.

Safety will be evaluated comparing incidence 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 glaucoma, 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 drug 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 which 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 results.
• 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 (vitamins, herbal supplements, dietary supplements)within 2 weeks prior to dosing. Paracetamol and ibuprofen are acceptable.
• Participation in any clinical investigation within 12 weeks prior to dosing.
• Donation or loss of 400 ml or more of blood within 8 weeks prior to dosing.
• Significant illness within 2 weeks prior to dosing.
• Other protocol-defined inclusion/exclusion criteria may apply.