Intrathecal nicardipine for post-subarachnoid hemorrhage cerebral vasospasm: a pharmacokinetic study

Introduction: Cerebral vasospasm is a common complication following non-traumatic subarachnoid hemorrhage. Vasospasm is associated with the development of a secondary stroke, namely delayed cerebral ischemia. Intrathecal nicardipine is a treatment which holds promise in treating cerebral vasospasm and preventing delayed cerebral ischemia. However, the pharmacokinetics and systemic effects of intrathecally administered nicardipine have not been well described. Methods: In this observational prospective study, following informed consent, we enrolled 12 patients who were treated with IT nicardipine via an existing external ventricular drain as part of usual care (5mg q6-8h). Spontaneously draining cerebrospinal fluid (CSF) was collected hourly following the first dose and after a scheduled dose on the third day of treatment. Plasma samples were also obtained at time 0, one hour and prior to the next dose. Nicardipine concentration was measured using liquid chromatography-mass spectrometry. Frequent vital signs, including intracranial pressure (ICP) were also collected. Results: After the first dose, the concentration of nicardipine in the CSF peaked at 1-hour post-administration and gradually decreased over time. Negligible plasma concentrations were observed (< 0.1% compared to the peak CSF). The pharmacokinetic curve of IT nicardipine was similar between the first dose and the 3rd day dose, apart from a measurable concentration at time zero (171.6±145.2 pg/mL on day 3, vs. 1.9±3.7pg/mL on the first dose, p< 0.01). The CSF half-life was estimated at 113.4±40.8 minutes. On the 3rd day of treatment, trough concentrations were similar before and after the dose, suggesting approximate steady state (171.6±145.2 pg/mL pre-dose vs. 151.7±181.5 pg/mL post dose, p=0.8). Although transient increases in ICP were noted in about 40% of patients, the mean change in ICP was not statistically significant, nor were there significant hemodynamic change. Conclusions: Scheduled dosing of intrathecal nicardipine at doses used in clinical practice resulted in consistent peak and trough concentrations, without evidence of significant systemic absorption or systemic adverse effects. An approximate steady state was achieved within 3 days.