Bioavailability of Vagantin® Coated Tablets Relative to an Oral Methantheline Bromide Solution

The primary objective of the study is:

•To describe extent and rate of absorption of methantheline after single oral dose administration of Vagantin® coated tablets (Test) in comparison to a methantheline bromide solution (Reference)

The secondary objectives of the study are:

• To determine elimination the half-life of methantheline bromide
• To describe the effects of Test and Reference on salivation, accommodation, pupil response, blood pressure and heart rate
• to assess frequency and intensity of adverse drug reactions

Study Overview

• Status: Completed
• Conditions: Neurogenic Bladder
• Intervention / Treatment: Procedure: blood sampling; Drug: Vagantin®; Procedure: Measurement of salivation; Procedure: Measurement of accommodation; Procedure: Pupillometry; Drug: methantheline solution

Detailed Description

The quarternary anticholinergic compound methantheline bromide (diethyl-methyl [2-(9 xanthenyl carbonyloxy) ethyl] ammonium bromide) is marketed to treat neurogenic bladder instability. In comparison with atropine, it influences the parasympathetic nervous transmission more by ganglionic rather than peripheral muscarinic receptor blockade. Clinical effects after single therapeutic doses of 50-100 mg last for about 6 hours which is longer than after atropine. The drug relaxes smooth muscles of the gastrointestinal and urogenital tract. Furthermore, it inhibits bronchial, salivary and sweat glands secretion, lowers the production of gastric juice and disturbs accommodation.

There are no data available on the pharmacokinetic properties of methantheline in man. However, 25-50 mg intravenous methantheline seem to be equivalent to 50-100 mg p.o. with regard to the pharmacodynamic effects [Stille 1988].

Vagantin® is marketed as coated tablets containing 50 mg methantheline bromide. Because of the particular properties of methantheline (narrow therapeutic range, obviously erratic, incomplete and irregular absorption) and because of the national and international recommendations concerning the registration of drugs, Vagantin® must be evaluated with regard to its pharmacokinetic properties at least relative to a non-formulated form.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Mecklenburg-Vorpommern
    • Greifswald, Mecklenburg-Vorpommern, Germany, 17487
      • Department of Clinical Pharmacology at the University of Greifswald

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 43 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• age: 18 - 45 years
• sex: male and female
• ethnic origin: Caucasian
• body weight: ±20 % of normal weight (Broca)
• good health as evidenced by the results of the clinical examination and the laboratory check-up which are judged by the clinical investigator not to differ in a clinical relevant way from the normal state
• written informed consent

Exclusion Criteria:

• known hypersensitivity to the investigational products or to their adjuvants
• pollakisurie of cardial and renal reasons
• megacolon
• atonia of the gastrointestinal tract
• atonia or hypotonia of the urinary bladder
• tachycardiac arrhythmia
• subvesical bladder obstruction, especially benign prostatic hypertrophy
• narrow angle glaucoma
• glasses or contact lenses
• history of gastrointestinal diseases (except appendectomy)
• history of renal and/or hepatic diseases
• any disease known to modify absorption, metabolism or excretion of the drug under investigation
• liability to orthostatic dysregulation, faintings, or blackouts
• alcohol consumption more than 40 g/day
• smokers of more than 10 cigarettes per day
• special or uniform nutritional habits, e.g. vegetarians or under-caloric diet
• less than 14 days after last acute disease
• less than 14 days after last systemic or local drug administration or 10 times the half life of the respective drug (except hormonal contraceptives)
• blood donation within the last two months
• blocking period due to another clinical study with investigational products; however at least 4 weeks after the end of the study or 10 times the half life of the respective drug
• lack of willingness or inability to co-operate adequately
• HIV and HBV and drug screening positive or not performed (in case of a positive HIV-test, the volunteers must be informed by a physician in a personal conversation)
• lactation and pregnancy test positive or not performed

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Test; Pharmacokinetics and -dynamics after single dose administration of 2 coated tablets Vagantin® (coated tablets of 50 mg methantheline bromide)	Procedure: blood sampling; blood sampling before and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 16 hours after administration of study medication; Drug: Vagantin®; administration of 2 coated tablets Vagantin® (coated tablets of 50 mg methantheline bromide); Procedure: Measurement of salivation; Volume of salivary gland secretion was measured by chewing a 5 x 5 cm piece of PARAFILM "M"® (American Can Company, UK) for 5 min. Saliva was collected in glass tubes and the amount of the stimulated saliva was measured by weighing; Procedure: Measurement of accommodation; Accommodation was measured with the optometer according to Schober (Velhagen 1972); Procedure: Pupillometry; Pupil function was assessed with the pupillograph (Compact Integrated Pupillograph, AMTech, Weinheim, Germany). The following data were obtained: pupil diameter, response to defined flash stimuli
Active Comparator: Reference; Pharmacokinetics and -dynamics after single dose administration 100 ml methantheline solution (100 mg methantheline bromide)	Procedure: blood sampling; blood sampling before and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 16 hours after administration of study medication; Procedure: Measurement of salivation; Volume of salivary gland secretion was measured by chewing a 5 x 5 cm piece of PARAFILM "M"® (American Can Company, UK) for 5 min. Saliva was collected in glass tubes and the amount of the stimulated saliva was measured by weighing; Procedure: Measurement of accommodation; Accommodation was measured with the optometer according to Schober (Velhagen 1972); Procedure: Pupillometry; Pupil function was assessed with the pupillograph (Compact Integrated Pupillograph, AMTech, Weinheim, Germany). The following data were obtained: pupil diameter, response to defined flash stimuli; Drug: methantheline solution; administration 100 ml methantheline solution (100 mg methantheline bromide)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
area under the curve (AUC0-∞)	AUC0-∞ was assessed by the trapezoidal formula up to the last sampling time with a concentration above the limit of quantitation (AUC0-), and was extrapolated to infinity using standard techniques	0-16 h plasma concentration-time profile of methantheline after single oral administration
maximal plasma concentration (Cmax)	Cmax was obtained directly from the measured concentration-time curves	0-16 h plasma concentration-time profile of methantheline after single oral administration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
time of maximal plasma concentration (tmax)	tmax was obtained directly from the measured concentration-time curves	0-16 h plasma concentration-time profile of methantheline after single oral administration
terminal half-life (t½)	Half-life (t½) was evaluated by non-linear regression of the terminal slope	0-16 h plasma concentration-time profile of methantheline after single oral administration
volume of salivary gland secretion	Volume of salivary gland secretion will be measured by chewing a 5 x 5 cm piece of PARAFILM "M"® (American Can Company, UK) for 5 min. Saliva will be collected in glass tubes the volume of which will be measured be weighing	before and 0, 0.5, 1, 2, 3, 4, 6, 8, 12 hours after administration of study medication
Measurement of accommodation	Accommodation will be measured with the optometer according to Schober (Velhagen 1972)	before and 0, 1, 2, 3, 4, 6, 8, 12 hours after administration of study medication
Pupil function	Pupil function will be assessed with the pupillograph (Compact Integrated Pupillograph, AMTech, Weinheim, Germany). The following data will be obtained: pupil diameter, response to defined flash stimuli	before and 0, 1, 2, 3, 4, 6, 8, 12 hours after administration of study medication

Collaborators and Investigators

• Sponsor: University Medicine Greifswald
• Collaborators: RIEMSER Arzneimittel GmbH

Publications and helpful links

General Publications

• Muller C, Lotsch J, Giessmann T, Franke G, Walter R, Zschiesche M, Siegmund W. Relative bioavailability and pharmacodynamic effects of methantheline compared with atropine in healthy subjects. Eur J Clin Pharmacol. 2012 Nov;68(11):1473-81. doi: 10.1007/s00228-012-1286-6. Epub 2012 Apr 21.

Study record dates

Study Major Dates

• Study Start: October 1, 1999
• Primary Completion (Actual): November 1, 1999
• Study Completion (Actual): January 1, 2000

Study Registration Dates

• First Submitted: September 1, 2011
• First Submitted That Met QC Criteria: September 2, 2011
• First Posted (Estimate): September 5, 2011

Study Record Updates

• Last Update Posted (Estimate): September 5, 2011
• Last Update Submitted That Met QC Criteria: September 2, 2011
• Last Verified: September 1, 2011

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Accommodation, Ocular; Reflex, Pupillary; Salivation
• Additional Relevant MeSH Terms: Nervous System Diseases; Urologic Diseases; Urinary Bladder Diseases; Neurologic Manifestations; Urinary Bladder, Neurogenic; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Muscarinic Antagonists; Cholinergic Antagonists; Cholinergic Agents; Methantheline
• Other Study ID Numbers: BAMB0199