Pharmacology, toxicology and clinical safety of glycopyrrolate

• Published in: Toxicology and applied pharmacology Vol. 370; pp. 154 - 169
• Main Authors: Chabicovsky, Monika, Winkler, Swantje, Soeberdt, Michael, Kilic, Ana, Masur, Clarissa, Abels, Christoph
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2019
• Subjects: Administration, Inhalation; Administration, Oral; Administration, Topical; Animals; Carcinogenicity Tests; Cholinergic Antagonists; Female; Glycopyrrolate; Glycopyrrolate - pharmacokinetics; Glycopyrrolate - pharmacology; Glycopyrrolate - therapeutic use; Glycopyrronium; Humans; Hyperhidrosis - drug therapy; Male; Molecular Structure; Mutagenicity Tests; Pharmacokinetics; Pharmacology; Pulmonary Disease, Chronic Obstructive - drug therapy; Reproduction - drug effects; Safety; Toxicology; FDA; ACh; mAChR; CNS; Glycopyrrolate; Pharmacology; LAMA; CHO; ICH; Toxicology; PTY; nAChR; EMA; Safety; Pharmacokinetics; Glycopyrronium; COPD
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2019.03.016

The clinical use of the anticholinergic glycopyrrolate dates back to the early 1960s when it was first approved in the U.S. Since then, oral and inhalation formulations have been developed as therapeutic agents inhibiting the muscarinic acetylcholine receptor in various indications including chronic obstructive pulmonary disease (COPD), excessive salivation, and peptic ulcers. More recently, topical formulations of glycopyrrolate (GPB, also known as glycopyrronium bromide) have gained interest as a treatment option for excessive sweating (hyperhidrosis). The U.S. Food and Drug Administration (FDA) approved the first topical glycopyrronium product for the treatment of hyperhidrosis in 2018. Glycopyrrolate, as a quaternary amine, shows minimal penetration of the blood brain barrier which limits CNS side effects. In addition, lack of phototoxicity, genotoxicity and carcinogenicity makes it suitable for chronic indications. The information on the nonclinical and clinical safety profile of glycopyrronium supporting various therapeutically approved uses has been obtained from published literature, our own data as well as summary documents issued by regulatory bodies. Collectively, these data support the conclusion that the benefits of glycopyrronium generally outweigh the risks in chronic use indications that require muscarinic receptor antagonism to provide therapeutic effects.