{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T20:10:19Z","timestamp":1788379819201,"version":"build-2803163510"},"reference-count":28,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T00:00:00Z","timestamp":1765152000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>\n                    Enterally-administered nimodipine is the only approved drug formulation available in the United States for treatment of patients with aneurysmal subarachnoid hemorrhage. Intravenous nimodipine is available in other countries but it contains a high concentration of ethanol that is irritating to the vasculature, can alter the effects of other medications, impair neurological assessments and is potentially harmful to the liver. We developed a sterile aqueous solution of nimodipine solubilized in polysorbate 80 micelles (GTX-104) that circumvents these problems. GTX-104 has been administered to 168 healthy human volunteers in 2 studies. We report the second study here, a phase 1, single center, randomized, 2-period cross over study that assessed the pharmacokinetics of GTX-104 and oral nimodipine capsules, which is the reference standard, in 58 healthy human volunteers. GTX-104 was administered for 72 hours as a continuous infusion of 0.15\u2009mg\/hour with a 30 minute bolus infusion of 4\u2009mg every 4 hours. Nimodipine capsules were administered orally at a dose of 60\u2009mg every 4 hours for 72 hours. The maximum plasma concentrations (geometric least square means) after the first dose of each formulation were similar (GTX-104: 63\u2009ng\/mL, n\u2009=\u200957 versus nimodipine capsules: 69\u2009ng\/mL, n\u2009=\u200956, ratio and 90% confidence interval [CI] of geometric LS\n                    <jats:sub>means<\/jats:sub>\n                    : 92% [90% CI: 82\u2013104%]). The areas under the concentration-time curves on the 3rd day at steady state also were the same (GTX-104: 492 ng*h\/mL, n\u2009=\u200956 versus nimodipine capsules: 462 ng*h\/mL, n\u2009=\u200955, ratio and 90% CI of geometric LS\n                    <jats:sub>means<\/jats:sub>\n                    : 106% [90% CI: 99\u2013114%]). The secondary pharmacokinetic parameters (daily maximum concentration at steady-state and time to maximum concentration) were also similar for the 2 formulations. The variability in PK parameters was less for GTX-104 compared to nimodipine capsules. The average oral bioavailability for nimodipine capsules was 7%. These results enabled a Phase 3 safety study of GTX-104 in humans with aneurysmal subarachnoid hemorrhage.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0323162","type":"journal-article","created":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T18:22:20Z","timestamp":1765218140000},"page":"e0323162","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Phase 1, randomized, crossover study comparing intravenous GTX-104 to oral nimodipine in healthy human subjects"],"prefix":"10.1371","volume":"20","author":[{"given":"Amresh","family":"Kumar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carrie","family":"D\u2019Andrea","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prashant","family":"Kohli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. George","family":"Kottayil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6642-6395","authenticated-orcid":true,"given":"James","family":"Longstreth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4024-8070","authenticated-orcid":true,"given":"R. Loch","family":"Macdonald","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,12,8]]},"reference":[{"issue":"10069","key":"pone.0323162.ref001","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1016\/S0140-6736(16)30668-7","article-title":"Spontaneous subarachnoid haemorrhage","volume":"389","author":"RL Macdonald","year":"2017","journal-title":"The Lancet"},{"issue":"7","key":"pone.0323162.ref002","article-title":"2023 guideline for the management of patients with aneurysmal subarachnoid hemorrhage: a guideline from the American heart association\/American stroke association","volume":"54","author":"BL Hoh","year":"2023","journal-title":"Stroke"},{"issue":"4","key":"pone.0323162.ref003","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1002\/phar.2791","article-title":"Comparison of nimodipine formulations and administration techniques via enteral feeding tubes in patients with aneurysmal subarachnoid hemorrhage: A multicenter retrospective cohort study","volume":"43","author":"SH Mahmoud","year":"2023","journal-title":"Pharmacotherapy"},{"issue":"2","key":"pone.0323162.ref004","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1007\/s12028-011-9605-9","article-title":"Critical care management of patients following aneurysmal subarachnoid hemorrhage: recommendations from the Neurocritical Care Society\u2019s Multidisciplinary Consensus Conference","volume":"15","author":"MN Diringer","year":"2011","journal-title":"Neurocrit Care"},{"issue":"3","key":"pone.0323162.ref005","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1007\/s12028-022-01493-4","article-title":"A Comparison Between Enteral and Intravenous Nimodipine in Subarachnoid Hemorrhage: A Systematic Review and Network Meta-Analysis","volume":"36","author":"F Geraldini","year":"2022","journal-title":"Neurocrit Care"},{"issue":"3","key":"pone.0323162.ref006","article-title":"Safety of Nimodipine in Critically Ill Aneurysmal Subarachnoid Hemorrhage Patients","volume":"4","year":"2021","journal-title":"Adv Prev Med Health Care"},{"issue":"1","key":"pone.0323162.ref007","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1007\/s12028-015-0230-x","article-title":"Nimodipine Dose Reductions in the Treatment of Patients with Aneurysmal Subarachnoid Hemorrhage","volume":"25","author":"N Sandow","year":"2016","journal-title":"Neurocrit Care"},{"issue":"4","key":"pone.0323162.ref008","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.3171\/2018.11.JNS182891","article-title":"The influence of nimodipine and vasopressors on outcome in patients with delayed cerebral ischemia after spontaneous subarachnoid hemorrhage","volume":"132","author":"A Pa\u013ea","year":"2019","journal-title":"J Neurosurg"},{"issue":"1","key":"pone.0323162.ref009","doi-asserted-by":"crossref","DOI":"10.1007\/s10143-023-02273-0","article-title":"Risks of nimodipine dose reduction during the high-risk period for delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage","volume":"47","author":"C Ditz","year":"2024","journal-title":"Neurosurg Rev"},{"key":"pone.0323162.ref010","doi-asserted-by":"crossref","DOI":"10.3389\/fneur.2017.00268","article-title":"High Compliance with Scheduled Nimodipine Is Associated with Better Outcome in Aneurysmal Subarachnoid Hemorrhage Patients Cotreated with Heparin Infusion","volume":"8","author":"A Wessell","year":"2017","journal-title":"Front Neurol"},{"issue":"4","key":"pone.0323162.ref011","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1007\/s00228-007-0267-7","article-title":"Early-phase pharmacokinetics of enteral and parenteral nimodipine in patients with acute subarachnoid haemorrhage - 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