https://orcid.org/0000-0001-6642-6395
Figures
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. 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 mg/hour with a 30 minute bolus infusion of 4 mg every 4 hours. Nimodipine capsules were administered orally at a dose of 60 mg 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 ng/mL, n = 57 versus nimodipine capsules: 69 ng/mL, n = 56, ratio and 90% confidence interval [CI] of geometric LSmeans: 92% [90% CI: 82–104%]). 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 = 56 versus nimodipine capsules: 462 ng*h/mL, n = 55, ratio and 90% CI of geometric LSmeans: 106% [90% CI: 99–114%]). 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.
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.
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].
Formulations of nimodipine approved for use in the US, Canada and some other countries include tablets, capsules and a solution, all administered orally while intravenous (IV) nimodipine is available in some other countries [3–5]. There are drawbacks with oral nimodipine including variable and low bioavailability (F), interference of absorption with feeding and high first-pass metabolism. Numerous medications induce or inhibit hepatic cytochrome enzymes that metabolize nimodipine, leading to reduced or increased nimodipine plasma concentrations. Furthermore, it is difficult to administer the capsules or tablets to patients who cannot swallow. The oral solution causes diarrhea [3,6]. As a result of these problems, peak plasma concentrations are highly variable and can lead to unpredictable hypotension, which can be dangerous for patients with aSAH. Although clinicians respond to hypotension by holding or reducing the dose of nimodipine or stopping it altogether, dose reductions are associated with increased risk of delayed cerebral ischemia and poor outcome [7–10].
Intravenous nimodipine could avoid these problems. Compared to solid dose forms, the IV formulation that is approved in the European Union, United Kingdom, China and some other countries, provides high F (approaching 100%) and more stable plasma concentrations and therefore potentially easier control of blood pressure (BP) [11,12]. However, nimodipine is practically insoluble in water and the existing IV nimodipine formulation contains 23.7% (v/v) ethanol and 17% (v/v) polyethylene glycol 400. Ethanol causes liver toxicity, irritation of the blood vessel at the infusion site and impairs assessment of neurological function [13,14]. This report describes an IV formulation of nimodipine (GTX-104) that avoids these problems. The report follows the CONSORT guideline [15].
Materials and methods
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.
First in human study (GTX-104–001)
GTX-104 was administered to 104 healthy adult human volunteers in a 4-part, single center, randomized, dose-escalation and crossover study to assess the safety, tolerability, pharmacokinetics (PK) and absolute F of GTX-104 compared to nimodipine capsules. Overall, GTX-104 was well tolerated. There was one treatment emergent adverse event (TEAE, infusion site extravasation with GTX-104) and no serious adverse events (SAEs). Population PK modeling from this GTX-104–001 study served as the basis for the dose regimen used in the study described herein.
Rationale, objectives and endpoints
The rationale for this study was to generate PK bridging data between IV GTX-104 and oral nimodipine capsules and to serve as a precursor to a GTX-104 Phase 3 study in patients with aSAH. The primary objective was to evaluate the relative F of IV GTX-104 versus nimodipine capsules at steady state in healthy human adults. The secondary objective was to compare safety and tolerability of these 2 formulations.
The primary study endpoints were maximum drug plasma concentration for the first dose on Day 1 (Cmax Day 1 0-4h) and area under the drug concentration-time curve (AUC) for 0–24 hours (h) on Day 3 (AUCDay 3 0-24h). Day 3 reflects PK steady state given the approximately 1.7–5.6 h elimination half-life of nimodipine [16]. Secondary PK endpoints were Cmax on Day 3 for all 6 doses given that day (Cmax Day 3 0-24h), total and apparent total body clearance from plasma and absolute F.
Safety endpoints included the incidence of TEAEs and SAEs, their severity and relationship to study drug and change from baseline to the end of the study in vital signs, physical examination, clinical laboratory evaluations (hematology, clinical chemistry and urinalysis) and 12-lead electrocardiogram (ECG).
This study adhered to consensus ethical principles from the Declaration of Helsinki and the Council for International Organizations of Medical Sciences International Ethical Guidelines. It followed applicable International Conference for Harmonization and Good Clinical Practice and Laboratory Guidelines. All subjects gave informed consent in writing. Subjects were free to withdraw from the study at any time for any reason, without prejudice to their medical care. The public and patients did not have any involvement in the design, conduct and reporting of this trial.
Study design
This was a Phase-1, single-center, randomized, 2-period crossover study in healthy, nonsmoking, normotensive male and female subjects between 18 and 55 years of age. There was no allocation concealment. Subjects had to be in good physical health, have normal cardiac conduction and function and have a body mass index between 18 and 32 mg/kg2. Subjects abstained from all medications except for the nimodipine formulations during the study. The inclusion and exclusion criteria were selected to ensure subjects were healthy and that they did not have gastrointestinal or cardiovascular diseases that would compromise safety or PK data from the study (Fig 2). The protocol is part of this submission (S1 File).
On the day prior to starting drug dosing (Day −1), subjects were admitted to the clinical research unit where they remained domiciled for the duration of the study (Fig 3). On Day −1, they were randomly assigned by a computer-generated schedule prepared before the start of the study, in a 1:1 ratio to receive GTX-104 in the first period and nimodipine capsules in the second period, or visa versa. The 2 periods were separated by washout period of at least 96 h. The rationale for the 96 h is that the plasma elimination half life of nimodipine capsules is 1.7–5.6 h and that of IV nimodipine is 0.9–1.5 h [16]. Therefore, 96 h is well beyond the typical washout period of 5 half lives. On Days 1–4 of each period, the study drug was administered at the same times each day (starting at 08:00 h on Day 1). Subjects fasted from 02:00–10:00 h so the doses at 04:00 and 08:00 h were administered in a fasting state. Standardized meals were provided at 10:00 h and then at approximately uniform times throughout the day.
Schematic drawing of the timeline of the study.
The study was initiated August 26, 2021 and completed February 24, 2022. Altasciences Company, Inc. conducted the study, including screening and enrolling subjects, administering study drugs, monitoring subjects, obtaining clinical data and laboratory samples, performing bioanalytical laboratory tests and writing the clinical study report (Mount Royal, Quebec, Canada). All study source documents and the electronic case report forms are retained by Altasciences. The Sponsor was free to audit Altasciences at any time during the study. No amendments were made to the protocol once the study started.
Drugs
GTX-104 was administered for 72 h as a 30-minute infusion of 4 mg every 4 h plus a continuous infusion of 0.15 mg/h. The GTX-104 dosing regimen was chosen to be safe and predicted by population PK modeling using data from the previous GTX-104–001 study to match the Cmax and AUC for oral nimodipine capsules.
Nimodipine capsules (Nimotop®, reference formulation) were administered orally with 240 mL of water at a dose of 60 mg (two 30 mg capsules) every 4 h for 72 h.
Assessments
Blood samples for nimodipine PK were taken around the first dose and on the third day. For the first dose, samples were taken at 08:00 h before the first dose and then 20, 30, 45, 60, 80 minutes and 2, 3 and 4 h after the dose. These times were used before the start of the first dose of the first period and then before the first dose of the second period. On the third day, the same scheduling was done around all 6 doses for that day, spanning from 48 to 72 h from the first dose. Blood pressure was taken prior to the first dose of study drug which was Day 1 and Day 8 for the second study drug. On Day 3 (and Day 10), it was taken 1 h after dosing for the 08:00, 12:00, 16:00 and 20:00 doses. Otherwise vital signs and BP were taken approximately every 12 h. Subjects were monitored continuously for AEs and SAEs. Clinical laboratory evaluation was done at screening, Day −1 and at the end of the study. ECG was done at screening and at the end of the study.
Systolic and diastolic BP and heart rate changes were categorized based on whether they met one of 2 sets of criteria (Table 1).
Adverse events and medical monitoring were managed by Safe Harbor Pharmacovigilence, LLC, (Raleigh, North Carolina, USA). Adverse events were classified by system organ class and preferred term using the Medical Dictionary for Regulatory Activities, version 24.0 (Medrio database). The definitions and reporting of AE, TEAE, severity, seriousness and causality followed good clinical practice, the US government Federal Register (Code of Federal Regulations [CFR] Title 21, Part 312.32[a]) and International Conference on Harmonization guidelines. Laboratory and safety data were done in compliance with good laboratory practice. Relationship to study drug was determined by the study principle investigator based on clinical judgment, the Investigator Brochure and the nimodipine capsules prescribing information. Relationship was classified as unlikely (not related to study drug based on temporal relationship to study drug administration or for which other drugs, chemicals or underlying disease provide a plausible explanation) or possible/probable (related to study drug based on temporal proximity to study drug administration, possible or unable to be explained by other drugs, chemicals or underlying disease and for which information on drug withdrawal may be lacking, unclear or follows a reasonable response to drug withdrawal).
Nimodipine assay
Blood samples for PK measurements were collected in K2EDTA vacutainers. As soon as possible following blood collection, samples were centrifuged for 10 minutes at 4°C and 1500g. The plasma obtained was separated into 2 polypropylene tubes. The samples were frozen at −20°C until assayed. The time from blood sample collection to plasma aliquot storage was not to exceed 90 minutes. Plasma samples were assayed for nimodipine using high-performance liquid chromatography with tandem mass spectrometry. The lower and upper limits of quantitation were 0.20 and 200.0 ng/mL, respectively.
Sample size estimation
A model-based approach was used to estimate power and sample size. An in silico population PK model was developed using data from the previous phase 1 GTX-104–001 study. This model included effects of food on the absorption of oral doses and a significant diurnal variation in F for the oral formulation. Simulated subjects (n = 1000) were randomized to a 2-period (GTX-104 or nimodipine capsules) crossover. Day 1 (first dose) and Day 3 (steady state) simulated data were used to estimate the number of subjects needed for adequate power for the Cmax Day 1 0-4h and AUCDay 3 0-24h comparisons. The estimate for the within subject variance came from a mixed effects model that included fixed effects, treatment and a random effect for subject and period. Under the hypothesis that the 90% CI for the true geometric mean ratio was 1 (GTX-104/nimodipine capsules) included 1 and were within the bioequivalence limits of 80–125%, 49 subjects were estimated to provide a power of 0.85 (Cmax Day 1 0-4h) and > 0.99 (AUCDay 3 0-24h), to assess relative F of GTX-104 versus nimodipine capsules in a 2-period, 2-sequence crossover study. Although no strict bioequivalence assessment was required, power was estimated using typical bioequivalence criteria.
A sample size of 60 subjects was planned in order to have at least 50 completed subjects.
Statistical analysis
Safety was assessed on a safety population defined as all subjects who received at least 1 dose of study drug. The sample size above was not intended to provide adequate statistical power for hypothesis tests comparing GTX-104 and nimodipine capsules for the safety endpoints. The PK analysis was done on a PK population defined as all subjects who received at least one dose of study drug and had sufficient PK data to derive at least one PK parameter. Subjects who did not complete the sampling schedule or otherwise had important protocol deviations or events that could seriously affect the PK could be included in the PK analysis for only the PK parameters that were judged not to be affected by the missing sample(s) or deviations. Finally, since some PK endpoints were ratios of PK values from each treatment, an analysis population was defined as those subjects in the PK population who were evaluable for both treatments.
All demographics, clinical laboratory evaluations, vital signs, physical examinations, ECGs and other data were presented as listings and summary tables. The AEs and TEAEs were listings and summary tables by system organ class, preferred term, severity and relationship to study drug. All analysis, except PK, used SAS version 9.4 (Cary, North Carolina, USA).
Pharmacokinetics
Missing nimodipine plasma concentration values were not imputed and were considered missing. Values below the lower limit of quantification were replaced with zero. PK data from the PK population for non-ratio variables and the analysis population for ratios were analyzed using Phoenix® WinNonlin® (Certara, Montreal, Quebec, Canada). Tmax was analyzed descriptively. The natural logarithm transformed Cmax Day 1 0-4h, AUCDay 3 0-24h and Cmax Day 3 0-24h were used for all statistical inference and were analyzed using analysis of variance. Fixed factors included in the model were treatment received, the period at which it was given and the sequence in which each treatment was received. A random factor was added for the subject effect (nested within sequence). The treatment, sequence and period effects were evaluated at the 5% significance level. The 90% confidence intervals (CI) for the exponential of the difference in least-squares means (LSmeans) between each comparison was calculated for the log-transformed parameters (Cmax Day 1 0-4h, AUCDay 3 0-24h and Cmax Day 3 0-24h). These values were back-transformed to provide the geometric ratios and 90% CI.
Relative F of GTX-104 and nimodipine capsules was calculated using the ratio of geometric LSmeans with corresponding 90% CI calculated from the exponential of the difference between treatments for the natural log-transformed parameters Cmax Day 1 0-4h, AUCDay 3 0–24hr and Cmax Day 3 0-24h.
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. A third subject was excluded from the primary endpoint of AUCDay 3 0–24hr and the secondary endpoint of Cmax Day 3 0-24h because an unknown volume of a bolus infusion of GTX-104 on the second day of the first period leaked out of the IV and was not administered to the subject. Thus, the PK population was 56 GTX-104 and 55 nimodipine capsules and the analysis population was 55.
Pharmacokinetics
The geometric LSmean Cmax Day 1 0-4h for GTX-104 and nimodipine capsules were 63 ng/mL and 69 ng/mL (intra-subject coefficient of variation [CV]: 39%, Fig 4, Table 3). The ratio of geometric LSmeans for Cmax Day 1 0-4h was 92% (90% CI: 82–104%). The variability in Cmax Day 1 0-4h was lower for GTX-104 compared to nimodipine capsules (geometric CV: 26% versus 55%, respectively). F was 100% for GTX-104 and 7.2% for nimodipine capsules.
Mean ± standard deviation of plasma nimodipine concentration after the first dose of intravenous GTX-104 (4 mg bolus, n = 56) and oral nimodipine capsules (60 mg, n = 55).
The overall daily exposures on Day 3 (AUCDay 3 0-24h) were similar between GTX-104 and nimodipine capsules with geometric LSmeans of 492 ng*h/mL and 462 ng*h/mL, respectively (intra-subject CV: 22%, Fig 5). As with Cmax Day 1 0-4h, greater variability was observed for capsules compared to GTX-104 (geometric CV: 38% versus 16%, respectively). The ratio of geometric LSmeans for the AUCDay 3 0-24h was 106% (90% CI: 99–114%).
Mean ± standard deviation of plasma nimodipine concentration after each of the 6 doses of intravenous GTX-104 (4 mg boluses, n = 56) and oral nimodipine capsules (60 mg, n = 55).
The geometric LSmean Cmax Day 3 0-24h for GTX-104 was 78 ng/mL compared to 85 ng/mL for nimodipine capsules; however, the variability was lower following GTX-104 administration (geometric CV: 17% versus 41% for nimodipine capsules, respectively). These maximum exposures for the 2 nimodipine treatments were similar at steady state on Day 3, with the ratio and 90% CI of the geometric LSmeans for Cmax Day 3 0-24h being 92% (90% CI: 85%−100%). The variability in Cmax on Day 3 for GTX-104 was limited (geometric CV: 19–30%) over the 6 bolus doses, while Cmax for nimodipine capsules showed greater variability (geometric CV: 46–61%).
The geometric mean apparent total body clearance on Day 3 for GTX-104 was 56 L/h (geometric CV: 15%) and for nimodipine capsules it was 772 L/h (geometric CV: 38%). Based on the ratio of nimodipine clearance during GTX-104 administration and apparent clearance during nimodipine capsule administration, the average oral bioavailability of nimodipine capsules was 7% (geometric mean, geometric CV: 32%).
Nimodipine plasma concentrations increased rapidly following both GTX-104 and nimodipine capsule administration, with median Tmax values occurring 0.5 h after the first dose on Day 1 for both formulations (Table 4). On Day 3, median Tmax was approximately 0.5 h for both treatments although greater variability in the range was observed following oral dosing (Table 4).
Adverse events
Overall, 44 out of the 58 subjects (76%) who received GTX-104 reported 122 TEAEs while 33 out of the 56 subjects (59%) who received nimodipine capsules reported 92 TEAEs (Table 5). Drug-related TEAEs were similar between groups (36/58 [62%] of GTX-104 and 31/56 [55%] of nimodipine capsule subjects). Most TEAEs were mild in severity and considered related to study drug (GTX-104: 80%, nimodipine capsules: 87%). There were no serious AEs.
The most common system organ class affected was the nervous system, with 26 subjects (45%) reporting nervous system TEAEs following GTX-104 administration and 28 subjects (50%) following nimodipine capsule administration (Table 6). The most frequently reported TEAEs (reported by 2 or more subjects) were headache (GTX-104: 35%, nimodipine capsules: 36%), catheter site erythema (24%, 0%), somnolence (7%, 13%) and hot flushing (3%, 11%). Fewer gastrointestinal disorders were reported with GTX-104 than with nimodipine capsules (7% versus 16%, respectively) while more administration and sampling site events were reported with GTX-104 (41% versus 11%).
The severe TEAE occurred in a 30 year-old male with no medical history who was not taking any medications before entry into the study. On Day 1 of the first study drug cycle, the subject experienced syncope (reported term: fainted) following a catheter insertion attempt. This was before study drug (GTX-104) was administered. The event resolved immediately and was reported as an AE of syncope of severe intensity. During the second study drug cycle, the subject received 60 mg nimodipine capsules every 4 h between Day 8 and Day 11. The subject fainted at 14:15 on Day 11, approximately 2 h and 15 minutes after receiving the second daily dose and 1 h and 45 minutes prior to receiving the third daily dose of nimodipine capsules. The event resolved immediately and was reported as a TEAE of syncope of severe intensity. The Investigator considered the TEAE to be possibly related to drug administration. No concomitant medication was taken by the subject, and he completed the study per protocol.
Following administration of GTX-104, 38–41% (n = 39) subjects experienced hypotension 2 (Tables 2 and 7). These changes were relatively consistent over the 4 boluses studied. The frequency of hypotension 2 following administration of nimodipine capsules was 29–50% (n = 39, Table 7). Overall, the proportion of subjects experiencing hypotension 1 was 33% (n = 19) with GTX-104 and 45% (n = 25) with nimodipine capsules. Approximately the same number of subjects in each group developed tachycardia 2 (heart rate >100 or >10 beats per minute above baseline). There were no clinically significant changes in laboratory tests or ECGs.
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. Intravenous nimodipine is used in Europe, China and some other countries. The enteral formulations have limitations. The oral tablets and capsules cannot be swallowed by patients who are unconscious or intubated and methods to administer them through nasogastric tubes often result in inadequate dosing [3]. There is a risk of medication errors; fatalities have resulted from incorrectly injecting the liquid aspirated from capsules IV. An oral liquid formulation was developed to prevent this but it contains polyethylene glycol which causes diarrhea [3,6]. Bioavailability of oral dosage forms is poor. Only 2 reports of F in aSAH patients were found which reported a range of 3–28% in 36 patient [17,18]. Soppi, et al., were unable to detect nimodipine in the plasma of 5 of 8 aSAH patients despite receiving the drug enterally [11]. Nimodipine is metabolized by the CYP3A4 system and is thus subject to food effects in the intestines and to first pass effect in the liver, which are highly variable in patients with aSAH. Numerous medications induce or inhibit CYP3A4, leading to reduced or increased nimodipine plasma concentrations. This variability leads to side effects, principally hypotension, which is regarded as being detrimental to patients with aSAH.
If hypotension occurs, the dose of nimodipine is reduced. However, this may reduce its efficacy [7,10,19]. Ditz and colleagues retrospectively assessed the effect of nimodipine dose reduction in 205 patients during the high-risk period for cerebral vasospasm and delayed cerebral ischemia between 5 and 10 days following SAH [9]. Patients with reduction in nimodipine dosage had worse clinical and radiological grades and developed vasospasm and delayed cerebral ischemia significantly more often. They also were more likely to have unfavorable outcome.
An IV nimodipine formulation could circumvent several of these problems but one has never been approved in the United States. The currently available formulation contains high concentrations of alcohol and organic solvent (ethanol [23.7% v/v] and polyethylene glycol 400 [17% v/v]) that are not suitable for continuous IV infusion. It irritates blood vessels and has to be administered through a central venous catheter. The ethanol is associated with liver injury and it can hinder neurological assessments. It is administered by continuous IV infusion which does not replicate the sawtooth PK profile produced with the repeated dosing of nimodipine capsules. The importance of this PK pattern for efficacy is unknown, but in consultation with FDA scientists, a study design was adopted with the intent to demonstrate that an IV dosing regimen could produce a similar sawtooth pattern of exposure, including similar magnitudes of peak and total exposure, as oral capsules for the aSAH indication.
This points out a limitation of this study which is that no patients with aSAH were studied. It remains to be seen whether slightly less hypotension and PK variability of GTX-104 compared to nimodipine is also found in patients with aSAH and whether this has any effect on clinically-important endpoints like delayed cerebral ischemia and functional outcome.
This report describes an IV formulation of nimodipine that does not have toxic or undesirable excipients. A dose regimen was selected to match the PK profile of nimodipine capsules. This IV formulation, GTX-104, was administered to try to replicate the PK of nimodipine capsules. It was shown that Cmax Day 1 0-4h was similar following the first dose of both formulations with the ratio of geometric mean Cmax Day 1 0-4h being 92% (90% CI: 82%−104%). The AUCDay 3 0–24hr was measured on Day 3, which was taken to represent steady state. The cumulative exposures for the two nimodipine formulations were similar with the ratio of geometric means being 106% (90% CI: 99%−114%). The Tmax for the first dose and for all the doses on Day 3 was also the same for GTX-104 and nimodipine capsules. The most notable other finding was that all PK parameters were less variable for GTX-104 compared to nimodipne capsules.
The safety profile of GTX-104 was similar to nimodipine capsules other than more injection site adverse events with GTX-104. None of these were clinically important and are somewhat irrelevant in aSAH patients who are generally in intensive care units and routinely have multiple points of intravascular access. Hypotension is the main clinically important side effect of nimodipine. Hypotension, defined as systolic BP < 90 mmHg or diastolic BP < 60 mmHg, was less common with GTX-104 compared to nimodipine capsules. This was probably because there was less variability in Cmax with GTX-104. Since unpredictable Cmax is believed to cause hypotension with oral nimodipine, the more consistent Cmax could be advantageous for patients with aSAH given reports that BP variability is associated with unfavorable outcome after aSAH [20,21]. The American Heart Association guidelines on aSAH state that “Close hemodynamic monitoring and blood pressure management to minimize blood pressure variability are beneficial” [2].
It is possible that some instances of study drug effect on BP were not detected since scheduled BP measurements were 1 h after study drug administration. The nimodipine capsule prescribing information does not reveal any other consistent, common side effects of nimodipine [22]. Headache is perhaps one such side effect although in the setting of aSAH it is essentially ubiquitous regardless of nimodipine use.
Bioavailability of nimodipine capsules was approximately 7%. Although there was essentially 100% bioavailability with GTX-104, there was less risk of hypotension. This is probably due to the high protein binding of nimodipine leaving little free drug to act on vascular L-type calcium channels.
There is great interest in the use of nimodipine as intraarterial rescue therapy for angiographic vasospasm in patients with aSAH [23,24]. Nimodipine also is injected into the ventricles of these patients for the same purpose [25,26]. These treatments have undergone some study in randomized clinical trials but additional ones are needed to determine their safety and efficacy. GTX-104 warrants study for these routes of administration, and potentially for other diseases [27].
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). The secondary PK parameters of the daily Cmax at steady-state and Tmax values were also supportive of the PK comparability of the two formulations. The range of values observed for all PK parameters was wider for nimodipine capsules compared to GTX-104. The improved bioavailability, less frequent hypotension and more consistent PK suggest GTX-104 delivered IV has the potential to be a more convenient, efficient and controlled way to deliver nimodipine to patients with aSAH than currently available formulations. Moreover, GTX-104 could potentially reduce BP variability and improve the management of hypotension and vasospasm in SAH patients, all three of which have been associated with mortality and/or disability after aSAH. A phase 3 randomized clinical trial was completed in January, 2025 and the results are not available yet [28].
Supporting information
S1 File. Clinical Trial Protocol: A Phase 1, Randomized, Two-Period Crossover Study to Evaluate the Relative Bioavailability of Intravenous GTX-104 Compared to Oral Nimodipine Capsules at Steady State in Healthy Male and Female Subjects.
https://doi.org/10.1371/journal.pone.0323162.s001
(DOCX)
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