Sublingual epinephrine outcomes fall between manual injection, autoinjectors
Key takeaways:
- Recommendations for outcomes that fall between results with manual injection and autoinjectors come from the FDA.
- “Bracketed” outcomes included geometric mean peak exposure and time to maximum concentration.
Sublingual delivery of epinephrine achieved pharmacokinetic and pharmacodynamic results that were comparable with manual intramuscular injection and autoinjectors, according to a study published in Annals of Allergy, Asthma & Immunology.
These results indicate that sublingual epinephrine may be an effective, needle-free alternative for treating type I allergic reactions such as anaphylaxis, Carl N. Kraus, MD, FACP, chief medical officer, Aquestive Therapeutics, and colleagues wrote.
“Publicly available data show that current epinephrine autoinjector devices have critical limitations: low carry rates, needle-phobia barriers and more than desired administration errors,” Kraus told Healio.
The AQST-109 (Anaphylm, Aquestive Therapeutics) sublingual film delivers a novel epinephrine prodrug, the researchers said, as an alternative to other epinephrine treatments that rely on devices for delivery.
“No-device oral film AQST-109 addresses these issues with its postage stamp-sized design that weighs less than an ounce,” Kraus said. “The film dissolves rapidly on contact, requires no water and comes in weather-resistant packaging thinner than a credit card.”
Also, the researchers noted, the FDA has said that new epinephrine formulations should yield pharmacokinetic results that fall between those produced by manual epinephrine injection and epinephrine autoinjectors, also known as pharmacokinetic (PK) bracketing.
“AQST-109 utilizes an epinephrine prodrug intended to enhance chemical stability and absorption and to minimize vasoconstriction at the administration site, which can lead to a more consistent and predictable drug response,” Kraus said.
“This can overcome the bimodal PK distribution seen with traditional epinephrine injections, characterized by two peaks in the drug concentration-time profile,” he said.
The pair of randomized, open-label, crossover phase 1 clinical trials included 54 healthy adults aged 18 to 50 years who received 12 mg of epinephrine via AQST-109 or a 0.3 mg dose of epinephrine via a manual intramuscular injection (Belcher Pharmaceuticals) or an autoinjector including EpiPen (Mylan), an EpiPen generic equivalent (Teva Pharmaceuticals) or Auvi-Q (Kaléo).
During the 134 exposures, 22 (54.5% men; mean age, 38 years) received AQST-109; 27 (63% men; mean age, 38 years) received manual intramuscular injections, 27 (63% men; mean age, 38 years) received EpiPen, 29 (65.5% men; mean age, 37 years) received the EpiPen generic equivalent and 29 (65.5% men; mean age, 37 years) received Auvi-Q.
Geometric mean peak exposure for AQST-109, which was 497.9 pg/mL, fell between manual intramuscular injection at 391 pg/mL and the autoinjectors, which included 669.9 pg/mL for EpiPen, 620.7 pg/mL for generic EpiPen and 688.4 pg/mL for Auvi-Q.
The manual intramuscular injection and autoinjector exposure (partial area under the curve) values also bracketed the AQST-109 results at all time points between 10 minutes and 60 minutes after the dose, the researchers said, although AQST-109 and the autoinjectors had similar exposure levels during the first 30 minutes.
AQST-109’s results for median time to maximum concentration at 15 minutes also were bracketed by manual intramuscular injection at 50 minutes and the autoinjectors, with EpiPen at 10 minutes, generic EpiPen at 15 minutes and Auvi-Q at 30 minutes.
“This rapid onset could be critical in managing anaphylaxis if approved by the FDA, where a quick response is crucial,” Kraus said.
The researchers called the differences in time to maximum concentration between AQST-109 and manual intramuscular injection and between manual intramuscular injection and the autoinjectors all significant (P < .05).
Times to reach 100 pg/mL of plasma epinephrine concentration with AQST-109 were within 10 minutes of administration for 18 subjects (81.8%) and within 15 minutes for 20 subjects (90.9%).
Among subjects receiving intramuscular injections, 15 subjects (55.6%) reached 100 pg/mL within 10 minutes of administration and 16 subjects (59.3%) reached 100 pg/mL within 15 minutes.
All the subjects who received EpiPen achieved 100 pg/mL within 10 minutes and 15 minutes of administration. The subjects who received generic EpiPen included 26 (89.7%) who achieved 100 pg/mL within 10 minutes and 15 minutes of administration.
The Auvi-Q group included 26 subjects (89.7%) who achieved 100 pg/mL within 10 minutes of administration and 27 subjects (93.1%) who achieved 100 pg/mL within 15 minutes.
AQST-109 also achieved significantly higher systolic blood pressure peak effect at 26.3 mmHg after administration, the researchers said, compared with 10 mmHg for manual intramuscular injection and 13.5 mmHg for EpiPen, 10.5 mmHg for generic EpiPen and 11 mmHg for Auvi-Q.
Similarly, the researchers continued, AQST-109 achieved significantly higher median diastolic blood pressure peak effect at 12.5 mmHg, compared with –4.5 mmHg for manual intramuscular injection, –9.5 mmHg for EpiPen, –6.5 mmHg for generic EpiPen and –6 mmHg for Auvi-Q.
Median heart rate peak effects included 16.8 bpm for AQST-109, 12 bpm for manual intramuscular injection, 14 bpm for EpiPen and 13.5 bpm for generic EpiPen, although the researchers did not consider these differences significant, and 17.5 bpm for Auvi-Q, which the researchers considered comparable with AQST-109.
Also, AQST-109’s 9-minute median time to maximum effect for systolic blood pressure was shorter than the other delivery methods, including 34 minutes for manual intramuscular injection and 29 minutes for both EpiPen, generic EpiPen and Auvi-Q alike, but the researchers did not consider these differences to be significant.
AQST-109’s 7-minute median time to maximum effect for diastolic blood pressure was lower than the other delivery methods as well, including 39 minutes for manual intramuscular injection, 29 minutes for EpiPen and 34 minutes for generic EpiPen, which the researchers called significant differences, and 24 minutes for Auvi-Q.
Median times to maximum heart rates included 11 minutes for AQST-109, 39 minutes for manual intramuscular injection, 19 minutes for EpiPen, 9 minutes for generic EpiPen and 29 minutes for Auvi-Q, which the researchers did not consider significantly different.
“This is important because these hemodynamic changes are key to counteracting the effects of anaphylaxis,” Kraus said.
Based on these findings, the researchers concluded that AQST-109 rapidly delivered epinephrine into the bloodstream while falling between results produced by manual intramuscular injection and autoinjectors, meeting FDA guidelines, indicating that it could be an alternative for patients who face barriers in using injection-based delivery.
Aquestive has submitted its NDA for AQST-109 to the FDA and expects acceptance sometime during the second quarter of this year.
“Aquestive has begun phase 1 trials in children aged 7 to 17 years ( 30 kg) to evaluate safety and effectiveness in pediatric populations,” he said.
Carl N. Kraus, MD, FACP, can be reached at allergy@healio.com.
Perspective
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Undercarriage and underuse of epinephrine autoinjectors are common, and delayed epinephrine use is associated with increased morbidity and mortality. A 2022 study that surveyed 200 patients and caregivers found that 40% of respondents delayed use of injectable epinephrine. Reasons for hesitation included fear of pain, needle-based safety risks, and size of the device. Furthermore, a 2019 study of 2,000 survey participants indicated that half of respondents carried their epinephrine autoinjector device at all times. Based on these findings, one might conclude that needle-free epinephrine products could improve carriage, ease of use and convenience and provide a less invasive route of administration.
For ethical reasons, epinephrine products are only studied in healthy volunteers. To be considered for regulatory approval, novel epinephrine products must demonstrate that the delivery method behaves similarly in the body to injectable epinephrine. This includes factors such as absorption, distribution, metabolism and excretion. It is quite promising that sublingual administration of epinephrine was comparable to injection. It also is quite promising that the sublingual prodrug of epinephrine met the pharmacokinetic and PD results within the bracketed range of the FDA approved intramuscular/subcutaneous epinephrine products.
One size does not fit all when it comes to medication, and the food allergy community is eager to have multiple epinephrine delivery products from which to choose. Innovative delivery forms could increase patient carriage, improve ease of use and convenience, and decrease hesitancy, thereby improving morbidity and mortality.
Real-world evidence studies use data from real-world clinical practice to evaluate the effectiveness, safety and other benefits or risks of a drug or medical product. These data can be gathered from various sources, including electronic health records, claims data and registries, and it is analyzed to provide insights that complement or expand upon the findings of traditional clinical trials.
References:
Portnoy J, et al. J Allergy Clin Immunol Pract. 2019;doi:10.1016/j.jaip.2019.03.021.
Rooney E, et al. Ann Allergy Asthma Immunol. 2022;doi:10.1016/j.anai.2022.08.547.
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