No abstract

ulmonary arterial hypertension (PAH) is a rare and debilitating disease, characterized by an increase in pulmonary vascular resistance that ultimately leads to right heart failure and death. 1 When a definite cause can not be demonstrated, the condition is termed primary pulmonary hypertension (PPH), which predominantly affects women most commonly in their third decade of life. 2 No ethnic predisposition is apparent in the National Institutes of Health registry, and the proportions by ethnic group parallel those in the general population. 2 Similar pulmonary vascular lesions are produced by many illnesses such as scleroderma, human immunodeficiency virus infection, liver disease or the use of certain anorectic drugs, and these are now classified as types of PAH. 3 A limited number of innovative strategies for the treatment of PAH have been developed over the past decades, but their effectiveness is Circulation Journal Vol.69, February 2005 largely limited by their nonselectivity for the pulmonary vasculature and significant drawbacks have been reported. 5 Recently, it was shown that PAH is associated with increased concentrations of endothelin (ET)-1, a potent vasoconstrictor, in plasma and the lungs, 6,7 suggesting that inhibition of ET receptors is a potential therapeutic alternative for this life-threatening disorder. In fact, studies with Caucasian PAH patients have demonstrated significant clinical benefits of bosentan, a dual ET receptor antagonist. [8][9][10] In the present study, the effects of bosentan on cardiopulmonary hemodynamics, symptoms and functional capacity were assessed, as well as the 6-min walk test and the specific activity scale (SAS), in Japanese patients with PAH.The pharmacokinetics of bosentan are dose-proportional up to a dose of 500 mg and in Caucasians, the absolute bioavailability of bosentan is 50%, being mainly excreted via the bile in the form of metabolites. 11,12 However, ethnic differences in the pharmacokinetics of many drugs have been demonstrated. 13 Therefore, prior to the start of the clinical trial, the multiple-dose pharmacokinetics of bosentan were compared in Caucasian and Japanese subjects. Methods Comparative Study of the Ethnic Differences in the Pharmacokinetics of BosentanThis part of the study was performed at FOCUS GmbH

Tezosentan (T) is a dual endothelin (ET) receptor antagonist, formulated for parenteral use and excreted unchanged in bile. Since ET‐1 may play a role in the pathogenesis of ascites and portal hypertension, cirrhosis and its complications may form an indication for T. The objectives of this study were to explore the tolerability, pharmacokinetics, and pharmacodynamics of T in patients with moderate/severe liver cirrhosis (Child‐Pugh B‐C). Each patient (total n=25) received 2 consecutive 24‐h infusions of 0.2 and 1.0 or 1.0 and 5.0 mg/h of T or placebo. Blood pressure was monitored and blood samples were taken for measurement of T and ET‐1. T was well tolerated (mainly mild headache as adverse event) and induced small dose‐dependent reductions in blood pressure. T showed dose‐proportional, 2‐compartment pharmacokinetics: rapid distribution and slower elimination. Its exposure was dependent on the baseline bilirubin level. For bilirubin levels < 3 and 3.5–12 mg/dl, the exposure to T was 3.3 and 8.5 fold that in healthy subjects (historical control), due to reduced clearance. Compared to patients with acute heart failure, the relative exposure was 1.2 and 3.2 fold, respectively. Exposure to ET‐1 increased dose proportionally and an indirect response model could describe the relationship between T and ET‐1. The IC50 was independent of the severity of the disease. In conclusion, adjustment of the dosing regimen of T in cirrhotic patients, based on bilirubin levels, is warranted. Clinical Pharmacology & Therapeutics (2004) 75, P31–P31; doi: