A novel CRTH2 antagonist: Single- and multiple-dose tolerability, pharmacokinetics, and pharmacodynamics of ACT-453859 in healthy subjects

• Published in: Journal of clinical pharmacology Vol. 55; no. 7; p. 787
• Main Authors: Géhin, Martine, Strasser, Daniel S, Zisowsky, Jochen, Farine, Hervé, Groenen, Peter M A, Dingemanse, Jasper, Sidharta, Patricia N
• Format: Journal Article
• Language: English
• Published: England 01.07.2015
• Subjects: Acetates - administration & dosage; Acetates - adverse effects; Acetates - pharmacokinetics; Adolescent; Adult; Carbazoles - administration & dosage; Carbazoles - adverse effects; Carbazoles - pharmacokinetics; Dose-Response Relationship, Drug; Double-Blind Method; Eosinophils - metabolism; Female; Half-Life; Humans; Male; Middle Aged; Receptors, Immunologic - antagonists & inhibitors; Receptors, Prostaglandin - antagonists & inhibitors; Young Adult; pharmacokinetics; CRTH2; entry-into-humans study; ACT-453859; receptor internalization
• ISSN: 1552-4604
• DOI: 10.1002/jcph.478

The chemoattractant receptor-homologous molecule expressed on T-helper 2 cells (CRTH2) is a G-protein-coupled receptor for prostaglandin D2 , a key mediator in inflammatory disorders. In this randomized, double-blind, placebo-controlled study we investigated the single- and multiple-dose tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) up to a dose of 800 mg once a day of ACT-453859, a potent and selective CRTH2 antagonist. ACT-453859 was moderately rapidly absorbed and followed a biphasic elimination pattern, with an elimination half-life between 11 and 20 hours. Steady-state conditions were reached after 1 day, and ACT-453859 did not accumulate. Urinary excretion of unchanged ACT-453859 did not exceed 1.4% of the administered dose. Administration of ACT-453859 resulted in a dose-dependent blockadeof CRTH2 on the surface of eosinophils. The maximum PD effect of ACT-453859 was reached about 2.0 hours after dosing, which corresponded to the highest concentration at which PD were assessed. At steady state, 100 and 800 mg ACT-453859 once a day resulted in blockade of CRTH2 over 24 hours. In this entry-into-humans study, ACT-453859 showed good tolerability at all doses and a PK and PD profile compatible with once-daily dosing.