The impact of anaphylaxis on the absorption of intranasal epinephrine in anaesthetized non-naive beagle dogs.

Background: Epinephrine delivery via an intranasal spray (neffy) is being evaluated as an additional option to treat severe allergic reaction and may provide clinical benefit by reducing the time to dosing in community settings by avoiding needles. Given that hypotension is a hallmark symptom of severe allergic reactions, a preclinical study was conducted to evaluate the impact of this factor on epinephrine absorption via neffy. Objective: The objective of this study was to evaluate the absorption of epinephrine via neffy in a dog model of anaphylaxis with severe hypotension. Methods: Epinephrine absorption via neffy was evaluated in anesthetized beagle dogs under both normal conditions and hypotension associated with anaphylaxis. A total of 14 dogs (10 males and 4 females) were dosed with neffy, 1.0 mg, under normal conditions, followed by neffy, 1.0 mg, under conditions of anaphylaxis. Results: The mean maximum concentration of epinephrine was higher during anaphylaxis than under normal conditions (2,670 ± 2,150 pg/mL and 1,330 ± 739 pg/mL [P < .05]). Relative to normal conditions, anaphylaxis resulted in higher overall epinephrine exposure (area under the curve from 0 to 45 minutes = 54,400 ± 18,100 min × pg/mL and 34,300 ± 21,500 minutes × pg/mL [P < .05]), which is likely due to the increase in vascular permeability commonly observed during severe allergic reactions. Conclusion: Taken together with real-world evidence from nasal naloxone treatment for opioid overdose demonstrating that the reduced blood flow or hypotension associated with overdose does not appear to suppress naloxone's efficacy, the current findings demonstrate that epinephrine is well absorbed following neffy delivery during the hypotension associated with severe anaphylaxis reactions.

Rapid increases in epinephrine concentration following presumed intra-blood vessel administration via epinephrine autoinjector.

While epinephrine autoinjectors have been the standard of care for the out-of-hospital treatment of anaphylaxis, their use has been associated with potential cardiovascular risks including intravascular injection, resulting in rapid increases in blood pressure and pulse rate. ARS Pharmaceuticals, Inc conducted a clinical trial designed to assess the pharmacokinetics and pharmacodynamics of ARS-1, an intranasal epinephrine spray in development, compared to EpiPen in subjects with a documented history of seasonal allergies. During the conduct of this study, a presumed intrablood vessel injection following EpiPen administration by a medical professional was observed in a female subject. The subject reported palpitations within 1 minute of receiving EpiPen injection; at 4 minutes postinjection, blood pressure was 221/128 mmHg (baseline 118/79), and pulse rate was 71 (baseline 56). In contrast, across all subjects (N = 36) the mean maximum increases in systolic blood pressure, diastolic blood pressure, and pulse rate were 12.0 mmHg, 2.8 mmHg, and 16.3 bpm, respectively. When this subject was removed from the pharmacokinetic analysis, the mean epinephrine Cmax of the remaining subjects was 801.1 pg/mL after administration of EpiPen; however, at 4 minutes postinjection this subject had a plasma epinephrine level of 4390 pg/mL, a >6.3-fold increase, illustrating the risks that may be associated with out-of-hospital epinephrine injections that are included as warnings in the product labeling. Despite the potential risks associated with accidental intravessel injection, it is important to note that intramuscular administration of epinephrine is currently the best currently available out-of-hospital treatment for severe allergic reactions and anaphylaxis.

Pharmacokinetics/pharmacodynamics of epinephrine after single and repeat administration of neffy, EpiPen, and manual intramuscular injection.

BACKGROUND: Epinephrine is the first-line treatment for severe allergic reactions, and rapid treatment is associated with lower rates of hospitalization and death. Current treatment options (epinephrine auto-injectors and manual intramuscular injection) are considered cumbersome, and most patients/caregivers fail to use them, even during severe reactions. An intranasal epinephrine delivery device, neffy, has been designed to provide an additional option for patients/caregivers. OBJECTIVE: We sought to assess the comparative pharmacokinetics and pharmacodynamics of neffy 2.0 mg, EpiPen 0.3 mg, and manual intramuscular injection 0.3 mg. METHODS: This was a phase 1, randomized, 6-treatment, 6-period, 2-part crossover study in 59 healthy subjects. Pharmacokinetic and pharmacodynamic parameters following single and repeat doses of epinephrine were assessed before dosing and at various postdose intervals. RESULTS: The pharmacokinetic profile of neffy was bracketed by approved injection products, with a mean peak plasma level of 481 pg/mL, which fell between EpiPen (753 pg/mL) and epinephrine manual intramuscular injection (339 pg/mL). When dosed both once and twice, neffy resulted in more pronounced increases in pharmacodynamic parameters relative to EpiPen or manual injection. CONCLUSIONS: neffy's pharmacokinetic profile was bracketed by approved injection products, with pharmacodynamic responses that were comparable to or better than approved injection products. neffy is expected to be a safe and effective option, particularly for patients/caregivers who are reluctant to carry and use injection devices.

Pharmacokinetic and pharmacodynamic comparison of epinephrine, administered intranasally and intramuscularly: An integrated analysis.

BACKGROUND: Manual intramuscular epinephrine injection is the standard of care for treating severe allergic reactions and anaphylaxis. Epinephrine autoinjectors were approved on the basis of the assumption that their pharmacokinetic and pharmacodynamic profiles are equivalent to manual intramuscular injection; however, although there is emerging evidence for product-related differences in pharmacokinetic profiles, very little is known about the comparative pharmacodynamic profiles. OBJECTIVE: To compare pharmacokinetic and pharmacodynamic profiles of epinephrine delivered through manual intramuscular injection, autoinjectors, and intranasal spray. METHODS: This integrated analysis was based on data from 4 randomized cross-over phase 1 trials that compared the pharmacokinetics and pharmacodynamics of epinephrine using manual intramuscular epinephrine 0.3 mg injection, epinephrine 0.3 mg autoinjectors (Symjepi and EpiPen), and epinephrine 1 mg intranasal spray (neffy). RESULTS: Data from 175 participants showed that although neffy (1.0 mg intranasal spray) resulted in a maximum concentration (258 pg/mL) that was lower than or comparable with manual epinephrine intramuscular injection (254 pg/mL), Symjepi (438 pg/mL) and EpiPen (503 pg/mL), it led to comparable increases in systolic blood pressure (maximum effect [Emax], 16.9, 10.9, 14.9, and 18.1 mm Hg, respectively). The effect of neffy on diastolic blood pressure was also markedly more pronounced than that of other products (Emax, 9.32, 5.51, 5.78, and 5.93 mm Hg, respectively). CONCLUSION: Intranasal delivery of epinephrine using neffy increases systolic blood pressure more efficiently than do manual intramuscular injection and epinephrine autoinjectors, despite lower maximum plasma concentrations.

Evaluation of Pharmacokinetics and Dose Proportionality of Diazepam After Intranasal Administration of NRL-1 to Healthy Volunteers.

NRL-1 is a novel intranasal formulation of diazepam that is being evaluated as rescue medication in patients with epilepsy who experience bouts of increased seizure activity despite stable regimens of antiepileptic drugs. This phase 1, open-label, randomized, crossover study in healthy adult volunteers consisted of 3 single-dose periods (5, 10, and 20 mg) followed by a 2-dose period (2 × 10 mg) with a minimum 28-day washout between treatments. Blood samples were taken at prespecified time points after intranasal dosing, and bioanalytic analysis of diazepam and nordiazepam was conducted using a validated liquid chromatography-tandem mass spectrometry method. Plasma pharmacokinetic parameters were summarized using descriptive statistics, and dose proportionality (peak concentration [Cmax ] and area under the plasma concentration-time curve [AUC0-∞ ]) was evaluated based on a power model within a 90%CI of 0.84 to 1.16. Comparisons were also conducted between single 10-mg dose and multidose (2 × 10 mg) treatments. NRL-1 administration resulted in rapid diazepam absorption (median time to peak concentration 1.4-1.5 hours). Plasma concentration-time profiles showed similar patterns of exposure that appeared to be dose dependent, with Cmax of 85.6, 133.6, and 235.3 ng/mL for the 5-, 10-, and 20-mg doses, respectively, although the lower 90%CI for Cmax and AUC0-∞ exceeded dose proportionality criteria. The coefficient of variation ranged from 59% to 67% for Cmax and 48% to 56% for AUC parameters. Dose-normalized AUC0-∞ values were comparable between the 2 × 10-mg and single 10-mg doses. Treatment-emergent adverse events were consistent with those expected for diazepam, with transient somnolence the most frequent adverse event (94.4%). These results support NRL-1 as a potential therapy for managing seizure emergencies.