Plasma and Cerebrospinal Fluid Pharmacokinetics of Clazosentan and its Relationship to Delayed Cerebral Ischemia in Patients with Aneurysmal Subarachnoid Hemorrhage

Background: Clinical pharmacokinetic data on clazosentan, an Endothelin Receptor Antagonist, after aneurysmal subarachnoid hemorrhage (SAH), particularly data on cerebrospinal fluid (CSF), remain limited. In this study, we evaluated the plasma and CSF concentrations and CSF penetration rate of clazosentan over time, and investigated whether the temporal profile differed between patients with SAH with and without delayed cerebral ischemia (DCI).

Methods: Clinical data, plasma, and CSF samples from 37 patients (mean, 63.2 years) with aneurysmal SAH prospectively collected in the SeCAS registry (nine stroke centers in Mie Prefecture, Japan, 2023-2025) were retrospectively analyzed. All patients underwent aneurysm obliteration within 48 h of SAH onset and were subsequently treated with continuous intravenous clazosentan (10 mg/h), with simultaneous collection of plasma and CSF over time. Clazosentan concentrations in plasma and CSF at post-SAH days 0-3, 4-6, 7-9, and 10-12 were measured by quantitative liquid chromatography-tandem mass spectrometry, and the CSF penetration rate was calculated. Mixed-effect models for repeated measures were used to assess temporal changes and period-by-DCI interactions.

Results: DCI occurred in seven patients (18.9%). In the overall cohort, plasma clazosentan concentrations decreased over time (p = 0.010). CSF concentrations showed no significant temporal change (p = 0.190), whereas the CSF penetration rate increased over time (p < 0.001). The temporal profile of CSF penetration rate differed by DCI status (period-by-DCI interaction, p = 0.008). In pairwise comparisons, the CSF penetration rate at post-SAH days 10-12 was significantly lower in the DCI group (geometric mean ratio 0.3, 95% confidence interval 0.1-0.7, p = 0.008).

Conclusions: During continuous intravenous infusion of clazosentan after SAH, plasma clazosentan concentrations declined while CSF concentrations were maintained, resulting in an increased CSF penetration rate. Lower CSF penetration was observed at days 10-12 in patients who developed DCI, suggesting a potential association between the relative CSF exposure of clazosentan and DCI.