Relative bioavailability and pharmacodynamic effects of methantheline compared with atropine in healthy subjects
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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.
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).
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.
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.
KeywordsMethantheline bromide Atropine Pharmacokinetics Pharmacodynamics PKPD modelling
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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