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

Primary Purpose

Neurogenic Bladder

Status

Completed

Phase

Phase 1

Locations

Germany

Study Type

Interventional

Intervention

blood sampling

Vagantin®

methantheline solution

Measurement of salivation

Measurement of accommodation

Pupillometry

About this trial

This is an interventional basic science trial for Neurogenic Bladder focused on measuring Pharmacokinetics, Accommodation, Ocular, Reflex, Pupillary, Salivation

Eligibility Criteria

18 Years - 45 Years (Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

Department of Clinical Pharmacology at the University of Greifswald

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Test

Reference

Arm Description

Pharmacokinetics and -dynamics after single dose administration of 2 coated tablets Vagantin® (coated tablets of 50 mg methantheline bromide)

Pharmacokinetics and -dynamics after single dose administration 100 ml methantheline solution (100 mg methantheline bromide)

Outcomes

Primary Outcome Measures

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

maximal plasma concentration (Cmax)

Cmax was obtained directly from the measured concentration-time curves

Secondary Outcome Measures

time of maximal plasma concentration (tmax)

tmax was obtained directly from the measured concentration-time curves

terminal half-life (t½)

Half-life (t½) was evaluated by non-linear regression of the terminal slope

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

Measurement of accommodation

Accommodation will be measured with the optometer according to Schober (Velhagen 1972)

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

Full Information

NCT ID

NCT01429090

First Posted

September 1, 2011

Last Updated

September 2, 2011

Sponsor

University Medicine Greifswald

Collaborators

RIEMSER Arzneimittel GmbH

1. Study Identification

Unique Protocol Identification Number

NCT01429090

Brief Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

September 2011

Overall Recruitment Status

Completed

Study Start Date

October 1999 (undefined)

Primary Completion Date

November 1999 (Actual)

Study Completion Date

January 2000 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University Medicine Greifswald

Collaborators

RIEMSER Arzneimittel GmbH

4. Oversight

5. Study Description

Brief 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

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Neurogenic Bladder

Keywords

Pharmacokinetics, Accommodation, Ocular, Reflex, Pupillary, Salivation

7. Study Design

Primary Purpose

Basic Science

Study Phase

Phase 1

Interventional Study Model

Crossover Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

12 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Test

Arm Type

Experimental

Arm Description

Pharmacokinetics and -dynamics after single dose administration of 2 coated tablets Vagantin® (coated tablets of 50 mg methantheline bromide)

Arm Title

Reference

Arm Type

Active Comparator

Arm Description

Pharmacokinetics and -dynamics after single dose administration 100 ml methantheline solution (100 mg methantheline bromide)

Intervention Type

Procedure

Intervention Name(s)

blood sampling

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Vagantin®

Intervention Description

administration of 2 coated tablets Vagantin® (coated tablets of 50 mg methantheline bromide)

Intervention Type

Drug

Intervention Name(s)

methantheline solution

Intervention Description

administration 100 ml methantheline solution (100 mg methantheline bromide)

Intervention Type

Procedure

Intervention Name(s)

Measurement of salivation

Intervention Description

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

Intervention Type

Procedure

Intervention Name(s)

Measurement of accommodation

Intervention Description

Accommodation was measured with the optometer according to Schober (Velhagen 1972)

Intervention Type

Procedure

Intervention Name(s)

Pupillometry

Intervention Description

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

Primary Outcome Measure Information:

Title

area under the curve (AUC0-∞)

Description

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

Time Frame

0-16 h plasma concentration-time profile of methantheline after single oral administration

Title

maximal plasma concentration (Cmax)

Description

Cmax was obtained directly from the measured concentration-time curves

Time Frame

0-16 h plasma concentration-time profile of methantheline after single oral administration

Secondary Outcome Measure Information:

Title

time of maximal plasma concentration (tmax)

Description

tmax was obtained directly from the measured concentration-time curves

Time Frame

0-16 h plasma concentration-time profile of methantheline after single oral administration

Title

terminal half-life (t½)

Description

Half-life (t½) was evaluated by non-linear regression of the terminal slope

Time Frame

0-16 h plasma concentration-time profile of methantheline after single oral administration

Title

volume of salivary gland secretion

Description

Time Frame

before and 0, 0.5, 1, 2, 3, 4, 6, 8, 12 hours after administration of study medication

Title

Measurement of accommodation

Description

Accommodation will be measured with the optometer according to Schober (Velhagen 1972)

Time Frame

before and 0, 1, 2, 3, 4, 6, 8, 12 hours after administration of study medication

Title

Pupil function

Description

Time Frame

before and 0, 1, 2, 3, 4, 6, 8, 12 hours after administration of study medication

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

45 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Facility Information:

Facility Name

Department of Clinical Pharmacology at the University of Greifswald

City

Greifswald

State/Province

Mecklenburg-Vorpommern

ZIP/Postal Code

17487

Country

Germany

12. IPD Sharing Statement

Citations:

PubMed Identifier

22527350

Citation

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.

Results Reference

derived

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

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