Phase 1, randomized, crossover study comparing intravenous GTX-104 to oral nimodipine in healthy human subjects
Amresh Kumar, Carrie D’Andrea, Prashant Kohli, S. George Kottayil, James Longstreth, R. Loch Macdonald
Abstract
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.
Introduction
Subarachnoid hemorrhage (SAH) is a type of hemorrhagic stroke that is usually caused by a ruptured intracranial saccular aneurysm [1]. While the incidence is only about 6 per 100,000 population per year, the average age of those afflicted is almost 2 decades younger than for ischemic stroke, and the mortality approaches 50%. Outcomes for aneurysmal SAH (aSAH) have improved over time, although the only treatments shown to be effective in adequate, well-controlled clinical trials are nimodipine and repair of the ruptured aneurysm by coiling rather than clipping [2].
Materials and method
GTX-104
GTX-104 is a sterile, aqueous-based, clear, colorless to light yellow solution containing nimodipine (2 mg/mL). Inactive ingredients include ultrapure polysorbate 80 (USP), dehydrated alcohol (USP) and water for injection (USP). GTX-104 is diluted in commonly used IV solutions to obtain a solution for infusion containing nimodipine, 0.08 mg/mL. This dosing solution is composed of dispersed micelles of polysorbate 80 containing nimodipine and about 1.26% w/v alcohol (Fig 1). All of the excipients are generally recognized as safe.
Results
Fifty-eight subjects were enrolled, randomized and included in the safety population (Table 2; Fig 2). One subject was excluded from the PK and analysis populations but included in the safety population. They were replaced by a subject that contributed data to all populations. One subject received GTX-104 in the first period but did not receive any oral nimodipine capsules in the second period so they were included for GTX-104 PK population but excluded from the nimodipine capsule PK and analysis populations.
Discussion
Nimodipine is a dihydropyridine with a molecular weight of 418 g/mol that was developed in the 1970s as a vasodilator with specificity for the cerebral vasculature. It has and continues to be studied as a treatment for many diseases but currently has approval in North America for treatment of patients with aSAH. The formulations approved in the United States and Canada are administered enterally.
Conclusions
An IV formulation of nimodipine, GTX-104, that does not contain toxic excipients was developed. In this Phase 1 crossover design comparative study, GTX-104 and oral nimodipine capsules demonstrated largely similar results for the 2 primary endpoints (Cmax Day 1 0–4 hr and AUCDay 3, 0–24hr).
Citation: Kumar A, D’Andrea C, Kohli P, Kottayil SG, Longstreth J, Macdonald RL (2025) Phase 1, randomized, crossover study comparing intravenous GTX-104 to oral nimodipine in healthy human subjects. PLoS One 20(12): e0323162. https://doi.org/10.1371/journal.pone.0323162
Editor: Muhammad Mohsin Khan, Hamad Medical Corporation, QATAR
Received: April 10, 2025; Accepted: November 9, 2025; Published: December 8, 2025
Copyright: © 2025 Kumar et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper and its Supporting Information files.
Funding: The author(s) received no specific funding for this work.
Competing interests: The authors have declared that no competing interests exist.
