Ambrisentan is a novel, selective endothelin type A receptor antagonist that has been developed for the treatment of pulmonary arterial hypertension (PAH). The present paper reports the pharmacokinetics (PK) and safety of ambrisentan tablets when administered as single oral dose in healthy Japanese subjects and as repeated oral doses in Japanese PAH patients. When a single dose of ambrisentan was administered orally to healthy Japanese subjects under fasted conditions at three dose levels of 2.5, 5 and 10 mg, absorption was rapid, and maximum plasma concentrations, Cmax
, were reached in 2-2.5 hours. The Cmax
were 179±32 (SD), 362±43 and 767±91 ng/mL, and the AUC0→∞
were 1439±373, 2945±609 and 6894±1613 ng·hr/mL, following 2.5, 5 and 10 mg doses, respectively. Ambrisentan exposure increased in an approximately linear fashion with dose. A single oral dose of ambrisentan 10 mg was administered in fasted and fed states to assess the influence of food intake on the systemic absorption of this drug. Compared to the fasted state, Cmax
was reduced by approximately 17% following administration with food. However, there were no changes in AUC0→48
. The fraction of parent drug excreted into the urine up to 96 and 120 hours after dosing was less than 4.0% at the three dose levels. The safety and tolerability of ambrisentan was confirmed following single oral administrations under fasted and fed conditions of 2.5, 5 and 10 mg ambrisentan to healthy Japanese subjects.
Japanese PAH patients taking ambrisentan 5 mg once daily for 12 weeks were also studied. Cmax
at steady state were 674±197 ng/mL and 8337±4715 ng·hr/mL, respectively. Systemic ambrisentan exposure in PAH patients was higher than that in healthy subjects.