Clinical Pharmacology of Clazosentan, a Selective Endothelin A Receptor Antagonist for the Prevention and Treatment of aSAH-Related Cerebral Vasospasm

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.

Effect of Hepatic Impairment on OATP1B Activity: Quantitative Pharmacokinetic Analysis of Endogenous Biomarker and Substrate Drugs

“…This association was also seen with the endogenous biomarker (coproporphyrin‐I) and some intravenous drugs (clazosentan and tezosentan) where any possible non‐specific effects like intestinal efflux inhibition or CYP3A inhibition/induction can be ruled out. Notably, these three compounds show minimal metabolism with predominant elimination mechanism via biliary excretion of unchanged compound 15,33,34 . These findings are indicative of a reduction in OATP1B transport activity as the primary driver for the observed marked increase in plasma exposure for OATP1B substrate drugs.…”

The Role of ET-1 in Early Cerebral Microcirculation Changes after Subarachnoid Hemorrhage

“…ET-1 specifically binds to ETA, resulting in vasoconstriction and reduced blood flow. It can be seen in our experiment that SAH injury of endothelial cells leads to the release of ET-1 in large quantities, and the level of ET-1 in plasma also increases, and its content is positively correlated with SAH symptoms [ 15 ]. ET-1 does not change the resting CBF.…”

Optimal Course of Statins for Patients With Aneurysmal Subarachnoid Hemorrhage: Is Longer Treatment Better? A Meta-Analysis of Randomized Controlled Trials

“…The American Heart Association/American Stroke Association guidelines regarding 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) for aSAH are inconclusive, and potential values of statins in aSAH should still be explored (Connolly et al, 2012 ; Juif et al, 2020 ). The results of many trials are still controversial owing to the insufficient evidence from randomized controlled trials (RCTs) and the inconsistent results of the existing studies (Liu et al, 2013 ; Lei et al, 2014 ; Lizza et al, 2014 ; Sikora Newsome et al, 2015 ; Akhigbe et al, 2017 ; Shen et al, 2017 ).…”