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Macitentan is a dual endothelin(ET) receptor antagonist(ERA) with a high binding affinity and has been shown to cause sustained inhibition of ETA and ETB receptors 1) . The physicochemical properties of macitentan allow high penetration into tissues 2) . Moreover, macitentan has significantly slower receptor dissociation kinetics resulting in sustained receptor occupancy with binding time 15 times longer compared with currently approved ERAs 3) . These characteristics are consistent with the possibility of greater efficacy of macitentan compared with bosentan, another ERA, as shown by significantly reduced mean pulmonary artery pressure, inhibition of pulmonary arterial thickening and right ventricular hypertrophy, and prolonged survival in a rat model of pulmonary hypertension 2) . The pharmacokinetic(PK)profile of macitentan permits once daily dosing without affecting metabolizing enzymes or transporters, thereby avoiding significant drug-drug interactions 4) . The lack of propensity of macitentan to interfere with intrahepatic bile salt transport results in reduced risk of elevation of liver enzymes, which is a well known adverse event of bosentan 5) . Macitentan inhibits ETB receptors and reportedly improves reduced reabsorption of alveolar fluid 6) , thereby preventing pulmonary edema which is one of the complications of pulmonary hypertension 7) . In the SERAPHIN trial, the first event-driven, randomized, placebo-controlled outcome study of pulmonary arterial hypertension(PAH)conducted outside Japan, long-term administration of 3 or 10 mg macitentan significantly reduced the risk of morbidity and mortality 8) . Previous reports have shown no substantial difference in the standard of medical care for PAH between Japan and Western countries 7,9) . The PK of a single dose of 10 mg macitentan in healthy Japanese and Caucasian subjects were evaluated in a previous study 10) , but the dose-response, safety, and tolerability of repeated dosing of macitentan in the Japanese population have yet to be elucidated. In the context of safety evaluations, the effect of macitentan on ECG parameters has been comprehensively evaluated in Caucasian populations 11) . Therefore, this study was designed to determine the tolerability, safety (including ECG evaluations), PK, and pharmacodynamics (PD) of repeated 3 and 10 mg doses of macitentan in 16 Japanese subjects.

rinshou yakuri/rinshō yakuri

&lt;b&gt;Tolerability, Safety, Pharmacokinetics, and Pharmacodynamics of Macitentan, a New Endothelin Receptor Antagonist, in Healthy Japanese Male Subjects &lt;/b&gt;