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.

Study Overview

• Status: Unknown
• Conditions: Bioequivalency
• Intervention / Treatment: Drug: Darifenacin; Drug: Darifenacin

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 24
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Federico Santoro, MD; Phone Number: +541143794300; Email: santorof@elea.com
• Study Contact Backup: Name: Joanna Steimberg, MBA; Phone Number: +541143794330; Email: steimbej@elea.com

Study Locations

• Uruguay
  • Montevideo, Uruguay, 11600
    • Center for Clinical Pharmacology Research (CCPR) Bdbeq S.A. Hospital Italiano.
    • Contact: Francisco E. Estevez-Carrizo, M.D.; Phone Number: +59824876288; Email: francisco.estevez@bdbeq.com.uy
    • Contact: Mónica Cedrés, Pharm. B.; Phone Number: +59824876288; Email: mcderes@bdbeq.com.uy
    • Principal Investigator: Susana Parrillo, M.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 48 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Darisec(R) 7.5 mg	Drug: Darifenacin; Single dose 7.5 mg tablets of darifenacin; Other Names: Darisec; Muscarinic antagonist; Cholinergic antagonist; Cholinergic agent; Drug: Darifenacin; Single dose 7.5 mg tablets of Darifenacin; Other Names: Enablex; Cholinergic antagonist; Cholinergic agent; Muscarinec antagonist
Active Comparator: Enablex(R) 7.5 mg	Drug: Darifenacin; Single dose 7.5 mg tablets of darifenacin; Other Names: Darisec; Muscarinic antagonist; Cholinergic antagonist; Cholinergic agent; Drug: Darifenacin; Single dose 7.5 mg tablets of Darifenacin; Other Names: Enablex; Cholinergic antagonist; Cholinergic agent; Muscarinec antagonist

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Extent of absorption	Extent of absorption will be measured using the area under the plasma concentration of darifenacin vs time from time 0 to the last sample point (AUC0-t) and from time 0 to infinity (AUC0-inf.	72 hours
Rate of absorption	Rate of abosorption will be measured using peak concentration of darifenacin (Cmax)taken from the concentration vs. time curve.	72

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to peak concentration (tmax)	Tmax is the time elapsed from ingestion of darifenacin tablets to plasma peak concentration (Cmax)	72
Elimination rate constant (Ke)	The elimination rate constant is the fractional rate of drug disappearance form the peripheral compartement, measured in the log-linear elimination phase.	72 hours
Elimination Half-life (t1/2e)	t1/2e is the time in which the concentration in the log-linear elimination phase drops by half.	72 hours
Systemic clearance (Cls)	Cls is the amount of plasma volume units that are totally cleared of the drug in the unit of time.	72 hours

Collaborators and Investigators

• Sponsor: Center for Clinical Pharmacology Research Bdbeq S.A.
• Collaborators: Laboratorio Elea Phoenix S.A.
• Investigators: Study Director: Francisco E. Estevez-Carrizo, MD, Univerisity of Montevideo. Biomedical Science Center.Prudencio de Pena 2440, 11600 Montevideo. Uruguay; Principal Investigator: Susana Parrillo, M.D., Center for Clinical Pharmacology Research Bdbeq S.A., Br. Artigas 1632. c.p. 11600 Montevideo. Uruguay.

Publications and helpful links

General Publications

• Skerjanec A. The clinical pharmacokinetics of darifenacin. Clin Pharmacokinet. 2006;45(4):325-50. doi: 10.2165/00003088-200645040-00001.
• Croom KF, Keating GM. Darifenacin: in the treatment of overactive bladder. Drugs Aging. 2004;21(13):885-92; discussion 893-4. doi: 10.2165/00002512-200421130-00005.
• Staskin DR. Overactive bladder in the elderly: a guide to pharmacological management. Drugs Aging. 2005;22(12):1013-28. doi: 10.2165/00002512-200522120-00003.
• Kerbusch T, Wahlby U, Milligan PA, Karlsson MO. Population pharmacokinetic modelling of darifenacin and its hydroxylated metabolite using pooled data, incorporating saturable first-pass metabolism, CYP2D6 genotype and formulation-dependent bioavailability. Br J Clin Pharmacol. 2003 Dec;56(6):639-52. doi: 10.1046/j.1365-2125.2003.01967.x.
• Dmochowski RR, Appell RA. Advancements in pharmacologic management of the overactive bladder. Urology. 2000 Dec 4;56(6 Suppl 1):41-9. doi: 10.1016/s0090-4295(00)01020-7.

Study record dates

Study Major Dates

• Study Start: December 1, 2010
• Primary Completion (Anticipated): January 1, 2011
• Study Completion (Anticipated): February 1, 2011

Study Registration Dates

• First Submitted: October 26, 2010
• First Submitted That Met QC Criteria: October 26, 2010
• First Posted (Estimate): October 27, 2010

Study Record Updates

• Last Update Posted (Estimate): October 27, 2010
• Last Update Submitted That Met QC Criteria: October 26, 2010
• Last Verified: October 1, 2010

More Information

Terms related to this study

• Keywords: Healthy volunteers; Bioequivalence; Postprandial; Darifenacin
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Urological Agents; Darifenacin; Cholinergic Antagonists; Muscarinic Antagonists; Cholinergic Agents
• Other Study ID Numbers: BDBEQ_DFNLP/ELEA_010