Abstract
Aneurysmal subarachnoid hemorrhage (aSAH) may lead to cerebral vasospasm and is associated with significant morbidity and mortality. It represents a major unmet medical need due to few treatment options with limited efficacy. The role of endothelin-1 (ET-1) and its receptor ETA in the pathogenesis of aSAH-induced vasospasm suggests antagonism of this receptor as promising asset for pharmacological treatment. Clazosentan is a potent ETA receptor antagonist for intravenous use currently under development for the prevention of aSAH-induced cerebral vasospasm. The pharmacokinetics of clazosentan are characterized by an intermediate clearance, a volume of distribution similar to that of the extracellular fluid volume, dose-proportional exposure, an elimination independent of drug-metabolizing enzymes, and a disposition mainly dependent on the hepatic uptake transporter organic anion transport polypeptide 1B1/1B3. In healthy subjects, clazosentan leads to an increase in ET-1 concentration and prevents the cardiac and renal effects mediated by infusion of ET-1. In patients, it significantly reduced the incidence of moderate or severe vasospasm as well as post-aSAH vasospasm-related morbidity and mortality. Clazosentan is well tolerated up to the expected therapeutic dose of 15 mg/h and, in aSAH patients, lung complications, hypotension, and anemia were adverse events more commonly reported following clazosentan than placebo. In summary, clazosentan has a pharmacokinetic, pharmacodynamic, and safety profile suitable to become a valuable asset in the armamentarium of therapeutic modalities to prevent aSAH-induced cerebral vasospasm.
Highlights
Endothelin and Endothelin ReceptorsEndothelins are highly potent vasoconstrictors displaying a key role in fluid-electrolyte homeostasis as well as cardiovascular and neuronal function (Davenport et al, 2016)
This review focuses on the clinical pharmacokinetics (PK), pharmacodynamics (PD), as well as safety and tolerability of clazosentan, which is under development for the prevention of aneurysmal subarachnoid hemorrhage-induced vasospasm (Figure 1) (National Library of Medicine, 2020)
Vasoconstrictor across multiple organ systems and has been identified in the pathogenesis of, e.g., pulmonary arterial hypertension (PAH) (Chester and Yacoub, 2014), infectious diseases (Freeman et al, 2014) or cancers (Salani et al, 2000a; Salani et al, 2000b; Salani et al, 2002); ET-2 is expressed in the ovary at the time of ovulation when corpus luteum formation begins and induces contraction of ovarian smooth muscles; and ET-3 mediates either vasoconstriction via binding to the ETB receptor or vasodilation via release of nitric oxide (NO) and prostacyclin (Kawanabe and Nauli, 2011)
Summary
Endothelins are highly potent vasoconstrictors displaying a key role in fluid-electrolyte homeostasis as well as cardiovascular and neuronal function (Davenport et al, 2016). It has been demonstrated that changes in ET-receptor expression and function in the wall of cerebral arteries may be a causal factor for development of cerebral vasospasm (Behrouz and Sadat-Hosseiny, 2015) In this respect, it has been demonstrated that ET-1 concentrations increase in the cerebrospinal fluid (CSF) of patients with aSAH (Figure 2). Messenger ribonucleic acid expression levels of ETA and ETB increased in arteries incubated with hemorrhagic CSF in vitro (Thampatty et al, 2011; Cheng et al, 2018) These data suggest that blockade of ET receptors may be beneficial to prevent and treat vasospasm in patients with aSAH. This may be due to a more multidisciplinary approach in the acute management of aSAH involving, e.g., neurosurgeons, radiologists, and endovascular specialists
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