Pilocarpine-Induced Effects on Salivary Secretion as a Pharmacological Biomarker for Cholinergic Parasympathetic Activation.

Autor: Treijtel N; Department of Clinical Pharmacology and Experimental Development, Astellas Pharma Europe B.V. Leiden, The Netherlands., Groenendaal-van de Meent D; Department of Clinical Pharmacology and Experimental Development, Astellas Pharma Europe B.V. Leiden, The Netherlands., Michon I; Department of Clinical Pharmacology and Experimental Development, Astellas Pharma Europe B.V. Leiden, The Netherlands., Korstanje C; Drug Discovery Research, Astellas Pharma Europe B.V. Leiden, The Netherlands., Meijer J; Drug Discovery Research, Astellas Pharma Europe B.V. Leiden, The Netherlands., Francke K; PAREXEL International Berlin, Berlin, Germany., Grossmann M; PAREXEL International Berlin, Berlin, Germany., de Vries M; Department of Clinical Pharmacology and Experimental Development, Astellas Pharma Europe B.V. Leiden, The Netherlands.
Jazyk: angličtina
Zdroj: Clinical pharmacology in drug development [Clin Pharmacol Drug Dev] 2022 Jan; Vol. 11 (1), pp. 25-33. Date of Electronic Publication: 2021 Nov 26.
DOI: 10.1002/cpdd.1048
Abstrakt: Pilocarpine-induced salivary secretion could serve as a nontherapeutic target engagement biomarker in a clinical setting to test the activity of an M3 positive allosteric modulator (PAM). The potentiating effect on the reactivity of the M3 receptor to the agonistic effect of pilocarpine would support the mechanism of action of an M3 PAM in a variety of therapeutic areas. The aim of this study was to determine the optimal pilocarpine dose needed for evaluation of this potentiating effect. Therefore, the effects of pilocarpine on salivary secretion rate and its pharmacokinetics were explored at single doses of 2.5, 5, and 10 mg of pilocarpine or placebo. The study also explored the test-retest variability of the pilocarpine-induced effects on salivary secretion. Pilocarpine caused a reproducible, dose-related increase in overall and maximum salivary secretion rate, in line with pilocarpine exposure. Oral doses of pilocarpine from 2.5 to 10 mg were safe and well tolerated, consistent with the published safety profile. These results support the use of pilocarpine in single-dose pharmacological challenge studies. The recommended dose for evaluating M3 PAM activity would be between 2.5 and 5 mg, showing a small increase in salivary secretion rate with room for further increase due to PAM activation.
(© 2021, The American College of Clinical Pharmacology.)
Databáze: MEDLINE
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