Clazosentan: A Review of Subarachnoid Hemorrhage Data

Abstract

Clazosentan (Ro 61–1790, VML-588 or AXV-034) is a synthetic endothelin (ET)-receptor antagonist that was derived from one of the first nonselective synthetic ET-receptor antagonists, bosentan. The structural modifications were designed to increase selectivity for the ET_A receptor and optimize aqueous solubility, both of which were fulfilled. Selectivity is approximately 1000-fold greater for the ET_A receptor with a pA2 in the nanomolar range. The half-life in humans is less than 2 h and the main side effects are headache, nausea and vomiting in clinically important doses, although they are not reported to be a problem in target disease populations. Clazosentan reverses established vasospasm in dogs with subarachnoid hemorrhage (SAH) and in preliminary studies in humans. It also prevents vasospasm in the double hemorrhage model of vasospasm in dogs and significantly decreases angiographic vasospasm after aneurysmal SAH in humans. The doses required are in the range of 5 to 15 mg/h in humans and correspond to effective doses in animal studies. These doses are also associated with relevant plasma and cerebrospinal fluid concentrations of the drug. A dose-finding study of clazosentan for prevention of vasospasm after SAH in humans showed a significant dose-dependent decrease in vasospasm and was favorable enough to lead to a Phase III trial.

Keywords :

• clazosentan
• endothelin
• subarachnoid hemorrhage
• vasospasm

Financial & competing interests disclosure

R Loch Macdonald is a consultant to Actelion pharmaceuticals. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.