Objective: To evaluate the pharmacology, pharmacokinetics, clinical efficacy, and tolerability of tezosentan, a new intravenous endothelin (ET)-1 receptor antagonist.
Data sources: Literature was identified through a MEDLINE search (1990-June 2003) using the search terms endothelin-1, heart failure, RITZ, and tezosentan. References listed in articles and abstracts from scientific meetings were also used.
Study selection and data extraction: English-language literature reporting controlled animal and human clinical studies was reviewed to evaluate the pharmacology, pharmacokinetics, therapeutic use, and adverse effects of tezosentan. Clinical trials selected for inclusion were limited to those with human subjects and included data from animal studies if human data were not available.
Data synthesis: Tezosentan is a dual ET-1 receptor antagonist that has demonstrated efficacy in improving cardiac index and reducing pulmonary capillary wedge pressure in patients with acute, decompensated heart failure. Following infusion, tezosentan's plasma concentration approaches steady-state within the first 6 hours, with a relatively small volume of distribution (17 L) and clearance (39 L/h) that are dose independent. Tezosentan is excreted almost entirely unchanged via the bile (>95%), with the rest (<5%) excreted in the urine. Elimination can be explained by a biphasic profile that has a rapid elimination phase (half-life 6 min) followed by a slow phase (half-life 3 h) that accounts for distribution from tissues. The adverse event profile is significant for a higher incidence of headaches, nausea, and hypotension compared with placebo.
Conclusions: Phase II and III clinical trials have rendered mixed results for the efficacy and tolerability of tezosentan. A dose optimization trial yet to be published and an ongoing Phase III registration study will provide valuable data regarding the efficacy and tolerability benefits, as well as the morbidity and mortality, of tezosentan. Until then, tezosentan's role in the treatment of patients with acute heart failure will remain unclear.