AQST-109, a sublingual film containing a novel prodrug of epinephrine (DESF), is under development for the emergency treatment of Type 1 allergic reactions. The final formulation of AQST-109 was compared with epinephrine delivered by two different approved autoinjectors (EpiPen and Auvi-Q) or by manual injection (IM).
BACKGROUND:Epinephrine intramuscular (IM) autoinjector is a life-saving drug for the emergency treatment of immediate-type allergic reactions (type I). Nevertheless, it is sometimes applied incorrectly or underused because of short shelf life, high costs, fear of use, or inconvenience of carrying. FMXIN002, a nasal powder spray of epinephrine, was developed as a needle-free alternative. OBJECTIVE:To compare epinephrine pharmacokinetics, pharmacodynamics, and safety after the administration of the FMXIN002 nasal spray versus autoinjector. METHODS:An open-label trial was performed in 12 adults with seasonal allergic rhinitis without asthma. Epinephrine pharmacokinetics, pharmacodynamics, and safety were compared between FMXIN002 (1.6 mg and 3.2 mg) administered intranasally with/without a nasal allergen challenge and IM (0.3 mg) EpiPen. RESULTS:FMXIN002 3.2 mg, administered after a nasal allergen challenge, displayed a shorter Tmax than EpiPen (median: 2.5 minutes vs 9.0 minutes, statistically nonsignificant [NS]) and a significantly shorter time when the measured analyte concentration is 100 pg/mL during the absorption phase pg/mL (median: 1.0 minutes vs 3.0 minutes for FMXIN002, P < .02). Moreover, FMXIN002 3.2 mg administered after the challenge test has resulted in a doubling of the maximal measured plasma analyte concentration over the sampling period (1110 vs 551 pg/mL, NS); area under the curve from 0 to 8 hours was 56% higher (672 vs 431 hours pg/mL, compared with EpiPen, NS). Pharmacodynamic response was comparable at all treatments. FMXIN002 was well tolerated, and treatment-emergent adverse events (AEs) were mild, local, and resolved spontaneously. No AEs were reported after the administration of EpiPen in our study. FMXIN002 was stable for 2 years at room temperature conditions. However, variability in the pharmacokinetics (expressed in coefficient of variation) is high. Having a prior nasal allergen challenge results in a substantial increase and speed of absorption. CONCLUSIONS:Intranasal absorption of dry powder epinephrine is faster than EpiPen offering a clinical advantage in the short therapeutic window for the treatment of anaphylaxis. The FMXIN002 product offers a needle-free, pocket-size, safe, user-friendly, and stable alternative to epinephrine autoinjectors.
Intramuscular (IM) injection of epinephrine as first-line treatment for acute allergic reactions and anaphylaxis presents some challenges that can lead to incorrect administration or delays in use. AQST-109 is the first and only sublingual film using a novel prodrug of epinephrine (DESF) being developed for the same target indication as epinephrine injection in the emergency treatment of Type 1 allergic reactions. This study was conducted to compare the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of epinephrine following administration of sublingual DESF versus 0.3 mg IM injection. Twenty-four healthy adult volunteers received either 12mg of sublingual DESF or 0.3 mg IM of epinephrine, in replicate fashion. Following dose administration, blood samples were obtained, and PD parameters were monitored over 8 hours. The Cmax of the 12mg sublingual DESF was 274.3 pg/ml compared to 350.6 pg/ml for IM epinephrine. The median Tmax following DESF was 15 minutes, substantially faster than that from IM injection (50 min). Early exposure, as characterized by AUC0-10 and AUC0-30 were comparable for both treatments: 7.9 hr*pg/mL vs 9.4 hr*pg/mL and 56.7 hr*pg/mL vs 47.5 hr*pg/mL for DESF and IM injection, respectively. There were no clinically meaningful safety concerns after administration of DESF. These results suggest that sublingual DESF provides comparable levels of epinephrine to that of IM epinephrine and achieved an epinephrine plasma Tmax in a significantly shorter time frame. Preliminary work suggests that sublingual DESF is a safe, alternative treatment that would address major unmet needs in patients at risk of anaphylaxis.
AQST-109 is the first and only sublingual film using a novel prodrug of epinephrine (DESF) being developed for the same target indication as epinephrine injection in the emergency treatment of Type 1 allergic reactions. This study compared the pharmacokinetic parameters of epinephrine following three different administration procedures for DESF. Twenty-four healthy adult volunteers each received 12mg of DESF according to these procedures: 1) holding the film and saliva in the sublingual (SL) space for 4 minutes, then swallow saliva; 2) holding the film and saliva in SL space for 2 minutes, then swallow saliva and, 3) holding the film in SL space while swallowing saliva freely. Following DESF dose administration, pharmacokinetic samples were obtained over 8 hours. All administration procedures yielded rapid median Tmax values (12 min for 4-min hold time vs 15 min for both 2-min and saliva swallowing). Cmax was 354.6 pg/ml, 302.2 pg/ml and 207.5 pg/ml, respectively. Early exposure characterized by AUC0-10 and AUC0-30 were 12.5 hr*pg/ml and 79.7 hr*pg/ml; 9.4 hr*pg/ml and 75.4 hr*pg/ml; and 8.9 hr*pg/ml and 47.6 hr*pg/ml, respectively. All administration routes produced rapid clinically relevant epinephrine Tmax, Cmax and early exposure levels which outperformed the IM injection route. Holding saliva during administration enhanced early exposure. Not holding saliva still provides clinically meaningful levels but increase the risk of lower absorption relative to the other procedures.
PURPOSEThis open-label, single-dose, randomized, two-period, two-treatment, two-sequence, crossover study evaluated the comparative bioavailability between amphetamine extended-release oral suspension (treatment A: AMPH EROS, Dyanavel XR 2.5 mg/mL, 18.8 mg amphetamine base per 7.5 mL) and extended-release mixed amphetamine salts (treatment B: ER MAS, Adderall XR 30 mg capsules, equivalent to 18.8 mg amphetamine base per capsule) after a single dose in healthy adult subjects, under fasted conditions.METHODSThe crossover design allowed for intra-subject PK comparisons. Relative comparable bioavailability was determined by a statistical comparison of the AUC and Cmax parameters for both d- and l-amphetamine, where the geometric mean ratios for AUC and Cmax were within the 90% confidence limits (80.0%-125.0%) to determine comparable bioavailability between test products. Subjects in sequence 1 received treatment A followed by B; subjects in sequence 2 received treatment B followed by treatment A. PK samples were obtained at 0 (pre-dose) through 60 hours post-dose. The safety assessment was based on reported frequency and severity of adverse events.RESULTSThirty (30) subjects were enrolled and 28 completed. The mean age of subjects was 35 years, with a mean BMI of 25.9 kg/m2. Most subjects were Male (63.3%) and Black (56.7%). The geometric mean ratios for Cmax and all AUC measurements were within the 80-125% bound indicating comparable bioavailability between both test products. Both test products were generally well-tolerated with no serious AEs reported.CONCLUSIONSThe bioavailability of a single 7.5 mL dose of AMPH EROS 2.5 mg/mL was comparable to a single 30 mg capsule dose of ER MAS. AMPH EROS (both d- and l-amphetamine) showed equivalent peak and overall exposure to ER MAS under fasted conditions.FUNDINGTris Pharma, Inc.
