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

• Extent of Absorption. [ Time Frame: 72 hours ] [ Designated as safety issue: No ]
  Extent of absorption will be measured using the area under plasma concentrations of darifenacin vs. time from time 0 to the last sample point (AUC0-t) and from time 0 to infinity (AUC0-inf).
• Rate of Absorption [ Time Frame: 72 ] [ Designated as safety issue: No ]
  Rate of abosrption will be measured using the peak concentration of darifenacin (Cmax).

• Time to peak concentration (tmax) [ Time Frame: 72 hours ] [ Designated as safety issue: No ]
  Is the time elapsed from ingestion of darifenacin tablets to plasma peak concentration.
• Absorption Rate Constant(Ka) [ Time Frame: 72 hours ] [ Designated as safety issue: No ]
  The absorption rate constant is the fractional rate of drug disappearance from the intestinal tract, measured in the log-linear phase of drug absorption.
• Elimination Rate Constant (Ke) [ Time Frame: 72 ] [ Designated as safety issue: No ]
  The elimiminaiton rate constant is the fractional rate of drug dissapearance from the peripheral compartment, measured in the log-linear phase of elimination.

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.

• Drug: Darifenacin
  Single oral dose Darisec(R) 15.0 mg
  Other Names:

  • Muscarinic Antagonists
  • Cholinergic Antagonists
  • Cholinergic Agents
  • Enablex
  • Darisec
• Drug: Darifenacin
  Single oral dose Enablex(R) 15 mg

• Active Comparator: Enablex(R) 15 mg , single dose
  Intervention: Drug: Darifenacin
• Experimental: Darifenacin 15 mg tablets, single dose
  Intervention: Drug: Darifenacin

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.