A Site-Specific, Sustained-Release Drug Delivery System for Aneurysmal Subarachnoid Hemorrhage

Abstract

Nimodipine is the only drug approved for use by the Food and Drug Administration for improving outcome after aneurysmal subarachnoid hemorrhage (SAH). It has less than optimal efficacy, causes dose-limiting hypotension in a substantial proportion of patients, and is administered enterally 6 times daily. We describe development of site-specific, sustainedrelease nimodipine microparticles that can be delivered once directly into the subarachnoid space or cerebral ventricles for potential improvement in outcome of patients with aneurysmal SAH. Eight injectable microparticle formulations of nimodipine in poly(DL-lactide-co-glycolide) (PLGA) polymers of varying composition were tested in vitro, and 1 was advanced into preclinical studies and clinical application. Intracisternal or intraventricular injection of nimodipine-PLGA microparticles in rats and beagles demonstrated dose-dependent, sustained concentrations of nimodipine in plasma and cerebrospinal fluid for up to 29 days with minimal toxicity in the brain or systemic tissues at doses <2 mg in rats and 51 mg in beagles, which would be equivalent of up to 612-1200 mg in humans, based on scaling relative to cerebrospinal fluid volumes. Efficacy was tested in the double-hemorrhage dog model of SAH. Nimodipine-PLGA microparticles significantly attenuated angiographic vasospasm. This therapeutic approach shows promise for improving outcome after SAH and may have broader applicability for similar diseases that are confined to body cavities or spaces, are self-limited, and lack effective treatments.

Randomized, Open-Label, Phase 1/2a Study to Determine the Maximum Tolerated Dose of Intraventricular Sustained Release Nimodipine for Subarachnoid Hemorrhage (NEWTON [Nimodipine Microparticles to Enhance Recovery While Reducing Toxicity After Subarachnoid Hemorrhage])

“…NEWTON tested the hypothesis that intracranial delivery of EG-1962, which achieved high and sustained CSF concentrations in preclinical studies, would increase efficacy without compromising safety. 8 …”

“…These doses were based on preclinical studies and were allowed under an Investigational New Drug Application to the United States Food and Drug Administration and a Clinical Trial Application to Health Canada. 8 EG-1962 (100 mg nimodipine/mL [Evonik Industries, Birmingham, AL] suspended in hyaluronic acid [Fidia Farmaceutici SPA, Abano Terme, Italy]) was administered as one intraventricular injection. After reconstitution in the pharmacy, it was transported to the subject’s bedside and remixed.…”

“…6–8 We performed a randomized, controlled, dose-escalation study to determine the safety, maximum tolerable dose (MTD), pharmacokinetics, and clinical effects of EG-1962 in humans (NEWTON [Nimodipine Microparticles to Enhance Recovery While Reducing Toxicity After Subarachnoid Hemorrhage). 7 …”

MEK1/2 inhibitor U0126, but not nimodipine, reduces upregulation of cerebrovascular contractile receptors after subarachnoid haemorrhage in rats

“…In humans an intracranial dose of 400 μg/hour has been applied, which theoretically will give an initial concentration of 3.2μg/mL (7 μM) [27]. Furthermore, the peak nimodipine concentration in the CSF of dogs was 3 μg/mL (7 μM) after 100 mg slow release nimodipine polymer [28].…”

Nimodipine Reappraised: An Old Drug With a Future

“…A new platform for localized, sustained-release administration of nimodipine, (EG-1962; Edge Therapeutics) is being investigated in clinical trials [160]. Pharmacokinetic evaluation showed nimodipine release after administration consists of an initial burst followed by sustained release over 21 days [161]. The plasma concentrations after aSAH in dogs are equivalent to oral nimodipine, although with less dose-dependent fluctuation, and are maintained for the entire time window when DCI may develop.…”