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European Journal of Clinical Pharmacology

, Volume 68, Issue 11, pp 1473–1481 | Cite as

Relative bioavailability and pharmacodynamic effects of methantheline compared with atropine in healthy subjects

  • Christian Müller
  • Jörn Lötsch
  • Thomas Giessmann
  • Gerd Franke
  • Regina Walter
  • Michael Zschiesche
  • Werner Siegmund
Clinical Trial

Abstract

Objectives

Methantheline is a strong muscarinic receptor blocking drug used in the treatment of overactive bladder syndrome, hypersalivation and hyperhidrosis. To provide basic information on the pharmacokinetics, magnitude of pharmacodynamic (PD) effects and their correlations with plasma concentrations, we performed a clinical study in 12 healthy subjects receiving methantheline as immediate-release coated tablets (IR) or in watery solution (SOL) in comparison with atropine and placebo tablets.

Methods

The pharmacokinetics and influence of methantheline, atropine and placebo on salivation and accommodation and pupil function (pupillometry: diameter, response to light flash) were studied in a randomized, controlled study after the administration of 100 mg methantheline bromide as IR and in SOL (phase 1) and 1.0 mg atropine sulphate and placebo (phase 2).

Results

Methantheline reached maximum plasma concentrations of approximately 25 ng/ml after 2.5–3 h and was eliminated at an apparent half-life of approximately 2 h. There was no pharmacokinetic (PK) bioequivalence of methantheline IR and SOL. The ratio IR/SOL (90 % confidence interval) were 0.892 (0.532–1.493) for AUC0-∞ and 0.905 (0.516–1.584) for maximum plasma concentration. The PD effects of both forms were nearly equivalent with a IR/SOL ratio of 1.015 (0.815–1.262) for salivation, which is the most susceptible characteristic. Methantheline reduced salivation at a potency (methantheline concentration at half maximum effects, EC 50) of 5.5 ng/ml in accordance with it plasma concentration. The antimuscarinic effects observed after methantheline administration were stronger and persisted longer than those following the administration of atropine.

Conclusions

Methantheline is slowly absorbed but rapidly eliminated in humans, and it exerts a strong effect on salivation which is closely associated with its plasma concentrations following a standard sigmoid PD model. Immediate-release tablets and a watery solution of methantheline are equivalent in terms of major PD effects (salivation, pupil function, heart rate) despite its high PK variability.

Keywords

Methantheline bromide Atropine Pharmacokinetics Pharmacodynamics PKPD modelling 

Notes

Acknowledgements

The authors thank Mr. Danilo Wegner, Gitta Schumacher and Sabine Bade for excellent technical support. This work was supported by Riemser Arzneimittel AG, Greifswald.

Conflict of interest

Christian Müller, Gerd Franke and Regina Walter are employees of RIEMSER Arzneimittel AG, Greifswald. Werner Siegmund has been principal investigator in several clinical trials sponsored by RIEMSER Arzneimittel AG. All other authors declare that they have no conflict of interest.

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Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Christian Müller
    • 1
  • Jörn Lötsch
    • 2
  • Thomas Giessmann
    • 3
  • Gerd Franke
    • 1
  • Regina Walter
    • 1
  • Michael Zschiesche
    • 3
  • Werner Siegmund
    • 3
  1. 1.RIEMSER Arzneimittel AGGreifswaldGermany
  2. 2.Pharmazentrum Frankfurt/ZAFES, Institute of Clinical PharmacologyGoethe-UniversityFrankfurt/MainGermany
  3. 3.Department of Clinical Pharmacology, Center of Drug Absorption and Transport (C_DAT), University Medicine University of GreifswaldGreifswaldGermany

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