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

Abstract

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.

Efficacy and safety of setipiprant in seasonal allergic rhinitis: results from Phase 2 and Phase 3 randomized, double-blind, placebo- and active-referenced studies

“…Assessment of trough setipiprant plasma concentrations at the end of weeks 1 and 2 in the Phase 2 trial indicated that steady-state pharmacokinetics were consistently attained after 1 week of treatment across the dose range assessed, which is in accordance with previous data from healthy subjects [34, 36]. However, both mean and median trough setipiprant concentrations were lower with setipiprant 1000 mg b.i.d.…”

“…Previous clinical studies with setipiprant showed a relationship between trough plasma concentration and AUC τ (i.e., AUC during a dosing interval) [34] indicating that trough plasma setipiprant concentrations allow assessment of systemic drug exposure as well as treatment compliance. Trough plasma setipiprant concentrations were therefore used to assess systemic drug exposure and treatment compliance using a validated liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) assay, which had a lower limit of quantification (LLQ) of 1 ng/mL [36].…”

“…Preclinical studies have shown that setipiprant blocks the activation of eosinophils and basophils, and reduces the secretion of cytokines (IL-4, IL-5, and IL-13) by Th2 cells [33]. In clinical studies, setipiprant has been shown to be well tolerated at both single and multiple doses in healthy subjects [27, 34–36]. A multicenter, double-blind, placebo-controlled, proof-of-mechanism Phase 2 study in 18 adult male participants with mild allergic asthma (forced expiratory volume in 1 s [FEV 1 ] ≥70% predicted) demonstrated that setipiprant 1000 mg b.i.d.…”

Targeting the PGD2/CRTH2/DP1 Signaling Pathway in Asthma and Allergic Disease: Current Status and Future Perspectives

“…Setipiprant, an orally active and selective CRTH2 antagonist, has been evaluated in a single- and multiple-dose tolerability and pharmacokinetic study in healthy male subjects [74]. Setipiprant was rapidly absorbed and followed a biphasic elimination pattern with a half-life of 10–18 h. The steady-state condition was reached after 2–3 days and the drug was well tolerated, with headache reported as the most frequent adverse event.…”

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

“…In this entry‐into‐humans study, we investigated the tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single‐ and multiple‐ascending doses of this new compound in healthy subjects over a wide range of doses and in either the presence or absence of food. PK and PD after multiple doses of setipiprant, used as a comparator in view of its similar mode of action, were also investigated at 2 doses (500 and 1000 mg twice a day), the highest of which had previously shown positive results in a proof‐of‐mechanism study as well as in a phase 2 dose‐finding study (http://clinicaltrials.gov registration NCT01484119).…”