Pharmacokinetics, pharmacodynamics, tolerability and prediction of clinically effective dose of ACT-774312: A novel CRTH2 antagonist.

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, tmax was delayed by 1 hour and exposure to ACT-774312 slightly decreased. Full blockade (>90% of the maximum effect, Emax ) 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 Emax 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.

Pharmacokinetics of Macitentan in Patients With Pulmonary Arterial Hypertension and Comparison With Healthy Subjects.

Macitentan is a worldwide approved dual endothelin receptor antagonist that has demonstrated efficacy in the treatment of pulmonary arterial hypertension (PAH) in a phase 3 clinical trial, SERAPHIN, at a dose of 10 mg once daily. During this trial, trough plasma concentrations (Ctrough ) of macitentan and its active metabolite,  ACT-132577,  were obtained at steady state in 242 patients, indicating that mean Ctrough of both analytes was about 2-fold higher in PAH patients than in healthy subjects. To further investigate the pharmacokinetics (PK) of macitentan and its active metabolite, ACT-132577,  a 24-hour PK profile was recorded at steady state in 20 PAH patients in the open-label extension of SERAPHIN.  A cross-study comparison showed that although Ctrough in PAH patients is higher when compared with a historical reference group of healthy subjects, with geometric mean ratios of 1.45 and 1.36 for macitentan and ACT-132577, respectively, this does not translate to a significant difference in exposure expressed as maximum plasma concentration (Cmax ) or area under the plasma concentration-time curve over a dosing interval (AUCτ ). Geometric mean ratios for Cmax and AUCτ were 1.08 and 1.22, respectively, for macitentan and 1.24 and 1.31, respectively, for ACT-132577. Therefore, overall exposure at steady state to macitentan and ACT-132577 in PAH patients is considered similar to that in healthy subjects.