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

Neurogenic Bladder Clinical Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01429090
• Other study ID #: BAMB0199
• Status: Completed
• Phase: Phase 1
• First received: September 1, 2011
• Last updated: September 2, 2011
• Start date: October 1999
• Est. completion date: January 2000

Study information

• Verified date: September 2011
• Source: University Medicine Greifswald
• Contact: n/a
• Is FDA regulated: No
• Health authority: Germany: Federal Institute for Drugs and Medical Devices
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 12
• Est. completion date: January 2000
• Est. primary completion date: November 1999
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 45 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Neurogenic Bladder
• Urinary Bladder, Neurogenic

Intervention

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)
• methantheline solution
administration 100 ml methantheline solution (100 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
• Measurement of accommodation
Accommodation was measured with the optometer according to Schober (Velhagen 1972)
• 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

Locations

Country	Name	City	State
Germany	Department of Clinical Pharmacology at the University of Greifswald	Greifswald	Mecklenburg-Vorpommern

Sponsors (2)

Lead Sponsor	Collaborator
University Medicine Greifswald	RIEMSER Arzneimittel GmbH

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	area under the curve (AUC0-8)	AUC0-8 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	No
Primary	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	No
Secondary	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	No
Secondary	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
Secondary	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	No
Secondary	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	No
Secondary	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	No