Nimodipine pharmacokinetics after intraventricular injection of sustained-release nimodipine for subarachnoid hemorrhage

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  • 1 Division of Neurosurgery, St. Michael’s Hospital, Labatt Family Centre of Excellence in Brain Injury and Trauma Research, Keenan Research Centre for Biomedical Research and Li Ka Shing Knowledge Institute, Departments of Surgery and Physiology, University of Toronto, Ontario, Canada;
  • 2 Edge Therapeutics, Berkeley Heights, New Jersey;
  • 3 Department of Neurosurgery, University Hospital Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany;
  • 4 Integrated Medical Development, LLC, Princeton, New Jersey;
  • 5 Department of Neurosurgery, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany;
  • 6 Institute for Critical Care Medicine and Department of Neurosurgery, Mount Sinai Hospital, New York, New York;
  • 7 Department of Neurology, Henry Ford Health System, Detroit, Michigan;
  • 8 Department of Neurosurgery, University of Florida, Gainesville, Florida;
  • 9 Neurological Critical Care, Washington University School of Medicine, St. Louis, Missouri;
  • 10 Department of Neurosurgery, University of New Mexico School of Medicine, Albuquerque, New Mexico; and
  • 11 Neurological Surgery, University of Maryland Medical Center, Baltimore, Maryland
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OBJECTIVE

The objective of this study was to measure the concentration of nimodipine in CSF and plasma after intraventricular injection of a sustained-release formulation of nimodipine (EG-1962) in patients with aneurysmal subarachnoid hemorrhage (SAH).

METHODS

Patients with SAH repaired by clip placement or coil embolization were randomized to EG-1962 or oral nimodipine. Patients were classified as grade 2–4 on the World Federation of Neurosurgical Societies grading scale for SAH and had an external ventricular drain inserted as part of their standard of care. Cohorts of 12 patients received 100–1200 mg of EG-1962 as a single intraventricular injection (9 per cohort) or they remained on oral nimodipine (3 per cohort). Plasma and CSF were collected from each patient for measurement of nimodipine concentrations and calculation of maximum plasma and CSF concentration, area under the concentration-time curve from day 0 to 14, and steady-state concentration.

RESULTS

Fifty-four patients in North America were randomized to EG-1962 and 18 to oral nimodipine. Plasma concentrations increased with escalating doses of EG-1962, remained stable for 14 to 21 days, and were detectable at day 30. Plasma concentrations in the oral nimodipine group were more variable than for EG-1962 and were approximately equal to those occurring at the EG-1962 800-mg dose. CSF concentrations of nimodipine in the EG-1962 groups were 2–3 orders of magnitude higher than in the oral nimodipine group, in which nimodipine was only detected at low concentrations in 10% (21/213) of samples. In the EG-1962 groups, CSF nimodipine concentrations were 1000 times higher than plasma concentrations.

CONCLUSIONS

Plasma concentrations of nimodipine similar to those achieved with oral nimodipine and lasting for 21 days could be achieved after a single intraventricular injection of EG-1962. The CSF concentrations from EG-1962, however, were at least 2 orders of magnitude higher than those with oral nimodipine. These results supported a phase 3 study that demonstrated a favorable safety profile for EG-1962 but yielded inconclusive efficacy results due to notable differences in clinical outcome based on baseline disease severity.

Clinical trial registration no.: NCT01893190 (ClinicalTrials.gov).

ABBREVIATIONS AUC = area under the concentration-time curve; AUC0–14d = AUC from 0 to 14 days; CI = confidence interval; Cmax = maximum concentration; Css = steady-state concentration; EVD = external ventricular drain; GOSE = Glasgow Outcome Scale-Extended; LC-MS/MS = liquid chromatography-tandem mass spectrometry; NEWTON = Nimodipine Microparticles to Enhance Recovery While Reducing Toxicity After Subarachnoid Hemorrhage; PK = pharmacokinetics; SAH = subarachnoid hemorrhage; WFNS = World Federation of Neurosurgical Societies.

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Contributor Notes

Correspondence R. Loch Macdonald: St. Michael’s Hospital, University of Toronto, ON, Canada. rlochmacdonald@gmail.com.

INCLUDE WHEN CITING Published online December 6, 2019; DOI: 10.3171/2019.9.JNS191366.

Disclosures Edge Therapeutics, Inc., funded the study. Dr. Macdonald was an employee and Chief Scientific Officer of Edge Therapeutics, Inc. Drs. Hänggi, Mocco, Mayer, Hoh, Etminan, Diringer, Carlson, and Aldrich received consulting fees from Edge Therapeutics for serving on the steering committee for this trial and for advising Edge Therapeutics, Inc. Drs. Mayer and Aldrich are consultants and receive consulting fees from Actelion Pharmaceuticals, Ltd. Dr. Faleck was an employee of Edge Therapeutics. Drs. Strange and Miller are employees of Integrated Medical Development, LLC. Dr. Mocco reports being a consultant to Imperative Care, Cerebrotech, Viseon, Endostream, Rebound Therapeutics, and Vastrax; ownership in Blink TBI, Serenity, NTI, Neurvana, and Cardinal Consulting; and research support from Stryker, Penumbra, Medtronic, and MicroVention.

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