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Comparative Investigation of the Pharmacokinetics of Bosentan in Caucasian and Japanese Healthy Subjects

From Actelion Pharmaceuticals Ltd, Department of Clinical Pharmacology, Allschwil, Switzerland.

Bosentan is a dual endothelin receptor antagonist in development for the treatment of pulmonary arterial hypertension in Japan, whereas it is registered for this indication in Europe and the United States. The present study was conducted to compare the pharmacokinetics of bosentan in Caucasian and Japanese subjects. In a double-blind, placebo-controlled, ascending single-dose, 5-way crossover study, 10 healthy Caucasian and 10 Japanese subjects (1:1 male/female ratio) received single doses of 31.25, 62.5, 125, and 250 mg of bosentan or placebo. Pharmacokinetic profiles of bosentan and its pharmacologically active hydroxy metabolite, Ro 48-5033, were determined after each dose of bosentan. The pharmacokinetics of bosentan were similar and dose proportional in both ethnic groups. However, peak plasma concentration values of Ro 48-5033 were significantly greater in Japanese subjects (P < .05). This difference could not be explained by the lower body weight of the Japanese subjects. Females in both groups tended to have higher exposure to both bosentan and Ro 48-5033 than males. The results suggest that, based on pharmacokinetic grounds, no dose adjustment of bosentan is necessary when used to treat Japanese patients in comparison to Caucasian patients.

Key Words: Bosentan • endothelin receptor antagonist • Caucasian and Japanese subjects • pharmacokinetics

Address for reprints: Paul L. M. van Giersbergen, PhD, Actelion Pharmaceuticals Ltd, Department of Clinical Pharmacology, Gewerbestrasse 18, 4123 Allschwil, Switzerland.

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