Single‐ and multiple‐dose tolerability and pharmacokinetics of the CRTH2 antagonist setipiprant in healthy male subjects

Chemoattractant receptor‐homologous molecule expressed on T helper (Th) 2 cells (CRTH2) is a G‐protein‐coupled receptor for prostaglandin D₂ (PGD₂), a key mediator in inflammatory disorders such as asthma and allergic rhinitis. In this study, we investigated the single‐ and multiple‐dose tolerability and pharmacokinetics (PKs) of setipiprant, an orally active, potent, and selective CRTH2 antagonist. This randomized, double‐blind, placebo‐controlled study was performed in two parts in healthy male subjects. In study Part A, single oral doses of up to 2000 mg setipiprant or placebo were given to sequential groups of eight subjects each. Additionally, the impact of food on the PKs was investigated in one‐dose group. In study Part B, two groups of subjects received 500 or 1000 mg setipiprant or placebo b.i.d. during 5.5 days. At regular intervals, tolerability variables and plasma and urine levels of setipiprant were determined. Setipiprant was well tolerated after single‐ and multiple‐dose administration. Headache was the most frequently reported adverse event. No treatment effect on tolerability variables was observed. After single‐ and multiple‐dose administration, setipiprant was rapidly absorbed and followed a biphasic elimination pattern with an elimination half‐life between 10 and 18 h. Steady‐state conditions were reached after 2–3 days and setipiprant did not accumulate. Exposure to setipiprant was lower in the presence of food. Urinary excretion of unchanged setipiprant did not exceed 7% of the administered dose. In this entry‐into‐human study, setipiprant showed good tolerability and a favorable PK profile, thus warranting its development in the treatment of inflammatory disorders.