Cerebrospinal Fluid Pharmacokinetics of Nicardipine Following Intrathecal Administration in Subarachnoid Hemorrhage Patients

Abstract

ABSTRACTSubarachnoid hemorrhage (SAH) is a devastating type of stroke, leading to high mortality and morbidity rates. Cerebral vasospasm and delayed cerebral ischemia (DCI) are common complications following SAH and contribute significantly to the poor outcomes observed in these patients. Intrathecal (IT) nicardipine delivered via an existing external ventricular drain has been shown to be correlated with reduced DCI and improved patient outcomes. The current study aims to characterize population pharmacokinetic (popPK) properties of intermittent IT nicardipine. Following informed consent, serial cerebrospinal fluid (CSF) samples were obtained from 16 SAH patients (50.4 ± 9.3 years old; 12 females) treated with IT nicardipine every 6 hours (n=8) or every 8 hours (n=8), which were subject to high-performance liquid chromatography for measurement of its CSF concentration. Our popPK analysis showed that the CSF PK of IT nicardipine in the cohort was adequately described by a two-compartment model with a lag time, with reliable parameter estimates (relative standard error < 50%). The intracranial pressure influenced both the total clearance and the central volume. Calculated PK parameters were similar between q6h and q8h dosing regimens. Despite a small cohort of SAH patients, we successfully developed a popPK model to describe the nicardipine disposition kinetics in the CSF following IT administration. These findings may help inform future clinical trials designed to examine the optimal dosing of IT nicardipine.