New routes of administration for adrenaline in anaphylaxis

PARIS While anaphylaxis requires immediate administration of adrenaline via autoinjection, the use of this treatment is not optimal. Therefore, the development of new adrenaline formulations (both for intranasal, sublingual and transcutaneous routes) aims to facilitate the use of the drug and reduce the constant delays in administration by patients and caregivers. A summary of the research was presented at the 19th Congress of French-Speaking Allergology.

Anaphylaxis is a severe and potentially fatal immediate hypersensitivity reaction with highly variable and dynamic clinical presentation. It requires immediate recognition for immediate treatment with intramuscular (IM) adrenaline (in the anterolateral aspect of the mid-thigh).

One might think that this reflex is acquired, but in France, while the number of prescribed adrenaline autoinjectors (AAI) has been increasing for a decade, reaching 965,944 units in 2022, this first-line treatment not used much. Anapen (150, 300 and 500 g), EpiPen (150 and 300 g), Jext (150 g and 300 g) and Emerade (150, 300 and 500 g) are the four products marketed in France in 2024.

“Only 17.3% of individuals presenting to the emergency department in the Lorraine region used it in 2015,” said Catherine Neukirch, MD, a pulmonologist at Hpital BichatClaude Bernard in Paris, France, with rates of 11.3% for children and 20.3% for adults. .

Incidence of anaphylaxis on the rise

Approximately 0.3% (95% CI, 0.1–0.5) of the population will experience an episode of anaphylaxis in their lifetime. The incidence in Europe, for all causes, is estimated between 1.5 and 7.9 cases per 100,000 inhabitants per year. Although anaphylaxis is increasing, its associated mortality remains low, ranging between 0.05 and 0.51 per million per year for drugs, between 0.03 and 0.32 per million per year for foods, and between 0.09 and 0.13 per million per year for hymenoptera venoms. .

Data from the European Anaphylaxis Registry show that anaphylaxis manifests quickly after exposure to the allergen: 55% of cases occur within 10 minutes and 80% within 30 minutes. In addition, a biphasic reaction, which can occur up to 72 hours after exposure, is observed in < 5% of cases.

While a delay in the use of epinephrine is associated with a risk of increased morbidity and mortality, AAI significantly reduces error rates compared to manual treatments involving ampoules, needles and syringes. It also reduces the risks of associated panic. However, there are many obstacles to the use of adrenaline. Clinical symptoms of anaphylaxis can be misleading, especially if it appears without skin manifestations and urticaria, but only with acute bronchospasm. It may present as isolated laryngeal edema without digestive involvement, hypotension, or other respiratory problems.

Other limitations to the use of adrenaline include technical difficulties and the possibility of incorrect administration, the need for appropriate needle sizes for obese patients, needle phobia, the possible negative effects of adrenaline injections, the inability to carry two autoinjectors, the limitations associated with with heavy storage and transportation. as well as the need for training and practice.

“These factors contribute to the underuse of adrenaline by patients and caregivers,” Neukirch said, resulting in delays in needed administration.

Adrenaline treatment criteria?

An analysis published in 2023 based on pharmacovigilance data from 30 French regional centers from 1984 to 2022 included 42 reported cases (mean age, 33 years; 26% children) of reactions to AAI, which is probably an underestimate. . About 40% of AAI uses have occurred during anaphylaxis. The remaining 60% were caused outside reactions. The main reasons were accidental injections, mainly in the fingers and cases of non-activation of the autoinjector, underlining the importance of patient education.

In 2015, the European Medicines Agency requested pharmacological studies on injectable adrenaline in healthy volunteers. These studies include ultrasound measurements of bolus injection, pharmacokinetics (ie, absorption, distribution, metabolism and excretion) and pharmacodynamics (ie, drug effect and mechanism of action in the body), with accurate assessment of cardiovascular effects (eg .systolic and diastolic blood pressure and heart rate).

Among the information collected with the different products, ultrasound studies have shown a different localization of the adrenaline bolus (ie in muscle in patients with normal BMI and mainly in adipose tissue in patients with BMI indicating overweight and obesity). The consequences of this discovery are still unknown.

In a study with 500 g of Anapen, overweight or obese women showed different pharmacokinetic or pharmacodynamic profiles from those of normal weight men, with an increase in the area under the curve (0-240 min) and marked differences in beat time. the heart. curve.

IM administration of 0.5 mg produces rapid pharmacokinetic effects in normal-weight, overweight, or obese patients, with a second peak delay in the latter case. This delay probably results from the initial local vasoconstriction due to adrenaline.

Early peak plasma concentration occurs in 5-10 minutes for AAI, with a greater speed for Anapen and EpiPen.

Moreover, the size of the needle is not the most important factor. Rather, it is the strength and speed of the injection, which can vary depending on the AAI.

Also, the optimal plasma concentration of adrenaline for the treatment of anaphylaxis is not known; studies cannot be performed during anaphylaxis. In terms of pharmacokinetics, a small series found that increased skin or muscle thickness delays the absorption of EpiPen AAI.

Intranasal adrenaline

To facilitate the rapid use of adrenaline and to convince reluctant patients to retain and use adrenaline, intranasal, sublingual, or transcutaneous forms are under development.

Three intranasal forms of adrenaline are already well advanced, including Neffy from ARS Pharma, epinephrine sprays from Bryn Pharma, and Hikma and Oxero from Oragoo, which contains dry powder.

A comparison of intranasal adrenaline Neffy and AAI shows that the former has satisfactory pharmacokinetic and pharmacodynamic effects.

In a phase 1 randomized crossover study of 42 healthy adults comparing the pharmacokinetic effects of Neffy adrenaline (2 mg) and EpiPen (0.3 mg), as well as IM epinephrine 0.3 mg, several observations were made. For a single dose, the maximum concentration (C_maximum) of Neffy was lower than that of EpiPen.

However, with repeated doses administered 10 minutes apart, C_maximum of Neffy was higher than that of EpiPen. At this stage, the pharmacodynamic responses to intranasal products are at least comparable to those of products approved for injection.

A comparison of the pharmacodynamic effects, such as systolic and diastolic blood pressure and heart rate, of Neffy and AAI adrenaline concluded that the profile of Neffy is comparable to that of the EpiPen and superior to that of IM epinephrine.

In patients with a history of allergic rhinitis, adrenaline C_maximum appears to be increased, while the time to peak plasma concentration (T_maximum) is reduced. Low blood pressure does not prevent Neffy from being inhaled. Neffy is currently under review by US and European health authorities.

Intranasal inhalation of dry powder adrenaline appears to be faster than that of the EpiPen, thus providing a clinical advantage in the short therapeutic window for the treatment of anaphylaxis.

In an open-label trial of 12 adults with seasonal allergic rhinitis without asthma, the pharmacokinetics, pharmacodynamics, and safety of epinephrine were compared between FMXIN002 (1.6 and 3.2 mg) administered intranasally with or without nasal allergen challenge. , and IM. EpiPen 0.3 mg. Pharmacokinetics varied by patient. However, nasal FMXIN002 had a shorter T_maximuma doubled C_maximum after peak allergen challenge and a higher area under the curve at 8 hours post-administration compared to EpiPen. Pharmacodynamic effects comparable to those of EpiPen were observed 15 minutes to 4 hours after administration. Tolerance was good, with mild and local side effects. The dust seems to settle a little better in the nasal cavity. It remains stable for 6 months at 40 C and 75% relative humidity and for 2 years at 25 C and 60% relative humidity.

Sublingual film Adrenaline

AQST-109 is a sublingual film intended to allow the rapid administration of epinephrine 1, which is a prodrug of adrenaline. The product is the size of a postage stamp, weighs < 30 g and dissolves on contact with the tongue.

The EPIPHAST II study was a phase 1, multiperiod crossover study conducted in 24 healthy adults (age, 24-49 years) who were randomly assigned to receive either 12 or 0.3 mg of AQST-109 epinephrine manual IM in the first two periods. . All participants received a 0.3 mg EpiPen in the last period.

EpiPen 0.3 mg resulted in a higher C_maximum than AQST-109 12 mg. AQST-109 12 mg had the fastest mean T_maximum of 12 minutes. The areas under the curve of AQST-109 12 mg fell between those of EpiPen 0.3 mg and manual adrenaline IM 0.3 mg.

Early increases in systolic blood pressure, diastolic blood pressure, and heart rate were observed with AQST-109 12 mg. The changes were more pronounced with AQST-109 12 mg despite a higher C_maximum with EpiPen 0.3 mg.

Part 3 of the EPIPHAST study evaluated the effect of food exposure (ie, a peanut butter sandwich) on the pharmacokinetics of AQST-109 12 mg in 24 healthy adults. Oral food residues did not significantly affect pharmacodynamic parameters and no treatment-related side effects were reported.

The researchers concluded that the absorption of 12 mg of AQST-109 would not be altered from “real-world” situations if used with meals. “These results suggest that the sublingual film of adrenaline may be promising in real-world situations,” Neukirch said, particularly in cases of food allergy with recent ingestion of the allergic food.

Transcutaneous adrenaline

A transcutaneous form of adrenaline using the Zeneo device developed by Crossject, a company based in Dijon, France, comes in the form of an AAI that does not require a needle. This project, funded by the European Union, uses a gas generator to deliver the drug at very high speed through the skin in 50 milliseconds. This method allows prolonged storage of the drug.

Neukirch reported financial relationships with Viatris, Stallergnes, ALK, Astrazeneca, Sanofi, GSK and Novartis.

This story was translated by Medscape French Edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.