Clinical trial NCT01429090: Bioavailability of Vagantin® Coated Tablets Relative to an Oral Methantheline Bromide Solution
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Neurogenic Bladder
Keywords: Pharmacokinetics
Accommodation, Ocular
Reflex, Pupillary
Salivation
Lead sponsor: University Medicine Greifswald
Sponsor class: OTHER
Collaborators: name: RIEMSER Arzneimittel GmbH
First posted: 2011-09-05
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

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.

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

Primary outcomes:
measure: area under the curve (AUC0-∞)
timeFrame: 0-16 h plasma concentration-time profile of methantheline after single oral administration
measure: maximal plasma concentration (Cmax)
timeFrame: 0-16 h plasma concentration-time profile of methantheline after single oral administration
Secondary outcomes:
measure: time of maximal plasma concentration (tmax)
timeFrame: 0-16 h plasma concentration-time profile of methantheline after single oral administration
measure: terminal half-life (t½)
timeFrame: 0-16 h plasma concentration-time profile of methantheline after single oral administration
measure: volume of salivary gland secretion
timeFrame: before and 0, 0.5, 1, 2, 3, 4, 6, 8, 12 hours after administration of study medication
measure: Measurement of accommodation
timeFrame: before and 0, 1, 2, 3, 4, 6, 8, 12 hours after administration of study medication
measure: Pupil function
timeFrame: before and 0, 1, 2, 3, 4, 6, 8, 12 hours after administration of study medication
Other outcomes:
Locations:
city: Greifswald
country: Germany
facility: Department of Clinical Pharmacology at the University of Greifswald
state: Mecklenburg-Vorpommern
Study officials:
References:
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.