Epinephrine administered sublingually reaches therapeutic thresholds
March 02, 2022
3 minute read
PHOENIX — Epinephrine can achieve therapeutic plasma concentrations by sublingual administration, according to a study presented at the annual meeting of the American Academy of Allergy, Asthma & Immunology.
“Anaphylaxis is a medical condition that has faced a lack of innovation for decades,” John Oppenheimer, MD, clinical professor of medicine at Rutgers University UMDNJ School of Medicine and allergist at Pulmonary and Allergy Associates NJ, Healio told Healio.
“Epinephrine has been used for over a century, but epinephrine auto-injectors are often underused due to a variety of factors, including needle phobia, late administration and non-carriage,” said he declared.
An alternative to injections
Many at-risk patients refuse to fill their prescriptions for injectable forms of epinephrine such as the EpiPen (Viatris/Mylan Inc.), Oppenheimer continued, while many who get their prescriptions don’t wear the device.
“Therefore, a different treatment modality could address a significant unmet medical need resulting from autoinjector deficiencies and improve patient access, utilization, and therapeutic response,” Oppenheimer said.
Still, alternative routes of administration did not produce the rate and observed plasma levels (Cmax) that standard of care produces, Oppenheimer said. Aquestive Therapeutics then developed a polymer matrix-based sublingual film containing AQST-109, which is a prodrug of epinephrine, using the company’s PharmFilm technology.
The size of a postage stamp, the film dissolves on contact and is designed to be used in place of epinephrine injections in the emergency treatment of Type 1 allergic reactions, including anaphylaxis.
“Medical devices such as the EpiPen are often large, have temperature storage limitations, and require the patient or caregiver to be comfortable with an injection,” Oppenheimer said.
Aquestive Therapeutics used feedback from patients at risk for anaphylaxis and their caregivers and physicians that needle epinephrine auto-injectors are not optimal for administration.
“One of the most attractive attributes of the product for patients and parents of pediatric patients is that the medication is stored in a foil pouch that is similar in size and thickness to a business card. Also, as a clinician, I strongly believe that a significant difference is the oral application of the product,” Oppenheimer said.
“Given the product’s small size, portability, and needle-free delivery, the AQST-109 has the ability to dramatically improve how patients and caregivers manage anaphylaxis,” he said. he continued.
The phase 1 study was designed to provide the first human data for the film. It involved 12 healthy male volunteers who were randomly assigned to receive formulation one (F1) or two (F2) of AQST-109.
The researchers measured the volunteers’ systolic and diastolic blood pressure and heart rate before dosing and up to 6 hours after. Adverse events and local tolerance were also monitored.
Both F1 and F2 doses of AQST-109 were absorbed and rapidly converted to epinephrine with an observed median time to reach maximum drug concentration (Tmax) of 15 minutes. In previous studies, EpiPen dosing had a median Tmax of 22 minutes.
“In the study, AQST-109 sublingual film demonstrated consistent Tmax values in a narrower range than reported for injectable epinephrine,” Oppenheimer said. “Its range was narrower compared to the range of injectable epinephrine from both our historical data and published literature.”
Additionally, the 12 mg dose of F1 resulted in a geometric mean Cmax of 552 pg/mL, and the 12 mg dose of F2 resulted in a geometric mean Cmax of 762 pg/mL. The EpiPen dosage has a geometric mean Cmax of 341 pg/mL, according to previous studies.
“This is the first time that epinephrine has been shown to achieve therapeutic plasma concentrations after sublingual administration,” Oppenheimer said.
AQST-109 also produced results comparable to previous Auvi-Q (kaelo, Inc.) studies, the researchers added.
Additionally, it produced significant changes in blood pressure and heart rate that were comparable to epinephrine auto-injectors.
Doses of all formulations and levels were generally well tolerated with no serious adverse effects, significant medical events, or serious treatment-related adverse events.
Noting that AQST-109 produced pharmacokinetic (PK) and pharmacodynamic (PD) responses within the expected therapeutic range, the researchers concluded that AQST-109 showed promise as a viable alternative for the treatment of anaphylaxis.
Aquestive Therapeutics is now awaiting data from its three-part EPIPHAST pilot study, which will examine the PK and PD values of AQST-109 compared to epinephrine injections.
“EPIPHAST is designed to demonstrate important safety, tolerability and pharmacokinetic information regarding AQST-109 that will define the eventual dose and final formulation for a future bioequivalence study with epinephrine [intramuscular] injection,” Oppenheimer said.
Aquestive Therapeutics aims to complete the EPIPHAST study in the first half of 2022.
“I look forward to seeing the data and continuing the discussion on this exciting program,” Oppenheimer said.
- OppenheimerJ, et al. Summary L37. Presented at: AAAAI Annual Meeting; February 25-28, 2022; Phoenix (hybrid meeting).