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Pharmacokinetics, pharmacodynamics, tolerability and prediction of clinically effective dose of ACT‐774312: A novel CRTH2 antagonist
Author(s) -
Géhin Martine,
Lott Dominik,
Farine Hervé,
Issac Milena,
Strasser Daniel,
Sidharta Patricia,
Dingemanse Jasper
Publication year - 2019
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/bcpt.13197
Subject(s) - pharmacodynamics , pharmacokinetics , medicine , blockade , tolerability , pharmacology , antagonist , placebo , adverse effect , dosing , potency , receptor , chemistry , alternative medicine , pathology , biochemistry , in vitro
ACT‐774312 is an antagonist of the chemoattractant receptor‐homologous molecule expressed on T helper (Th) 2 cells (CRTH2), in development for the treatment of nasal polyposis or other allergic and type‐2 inflammatory diseases. Placebo, single doses of 1‐1000 mg, or multiple doses of 30‐500 mg either once or twice daily for 4 days of ACT‐774312 were administered orally to healthy subjects. The single‐ and multiple‐dose pharmacokinetics (PK) of ACT‐774312 were dose proportional and characterized by a time to attainment of maximum plasma concentrations between 1 and 3 hours and a terminal elimination half‐life of about 12 hours In the presence of food, t max was delayed by 1 hour and exposure to ACT‐774312 slightly decreased. Full blockade (>90% of the maximum effect, E max ) of CRTH2 as measured in a whole blood internalization assay was observed after 50 mg ACT‐774312 twice daily and lasted for at least 9 hours The relationship between ACT‐774312 concentration and CRTH2 blockade was described by a E max model. The estimated twice‐daily dose of ACT‐774312 at which full blockade of CRTH2 is achieved at trough in at least 80% of subjects was estimated at 109 mg. Administration of ACT‐774312 was safe and well tolerated at all doses. For none of the recorded adverse events, a relationship to dose was discerned, and there were no clinically relevant findings on the measured ECG, clinical laboratory and vital signs variables. The observed PK, pharmacodynamics and safety profile warrant further development of ACT‐774312.