Pharmacokinetics of intraventricular tissue plasminogen activator in aneurysmal subarachnoid hemorrhage patients

Background: Intraventricular hemorrhage (IVH) frequently complicates intracerebral or subarachnoid hemorrhage (SAH) and is associated with poor outcomes. Administration of intraventricular tissue plasminogen activator (TPA) accelerates blood clearance, but the optimal dosing interval is unknown. Methods: We randomly allocated patients with aneurysmal SAH and IVH treated with endovascular coiling and ventricular drainage to receive 2 mg intraventricular TPA or placebo every 12 hours (5 doses). CT scans were performed 12, 48 and 72 hours after initial administration and intracranial blood was quantified using SAH and IVH Scores. Cerebrospinal fluid (CSF) TPA and D-dimer levels were measured at baseline and 1, 6 and 12 hours after the first TPA dose using ELISA. Results: Median CSF TPA concentrations (with interquartile ranges) in seven TPA-treated patients were 525 (352-2129), 323 (233-413), and 47 (29-283) ng/ml, respectively, 1, 6 and 12 hours after drug administration. Peak concentrations varied markedly (401-8398 ng/ml). Two patients still had elevated levels (283-285 ng/ml) when the next dose was due. There were no hemorrhagic complications and no correlation between TPA concentration and D-dimer levels or rate of blood clearance. D-dimer concentration peaked at 6 hours and correlated strongly with radiographic IVH clearance (r=0.94, p=0.005) Conclusions: The pharmacokinetics of CSF TPA vary considerably between individual patients. Administration every 12 hours is an appropriate dosing interval.