Pharmacokinetic and pharmacodynamic comparison of epinephrine, administered intranasally and intramuscularly

Tanimoto, Sarina; Kaliner, Michael; Lockey, Richard F.; Ebisawa, Motohiro; Koplowitz, Luana Pesco; Koplowitz, Barry; Lowenthal, Richard

doi:10.1016/j.anai.2022.10.024

Cited by 20 publications

(7 citation statements)

References 14 publications

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“…Therefore, it is reasonable to assume that a t max of ≥ 30 minutes can be considered indicative of intramuscular absorption. This 30-minute timing coincides with the second peaks reported in previous publications 1,2,3,4,7,8 .…”

Section: Discussionsupporting

confidence: 90%

“…Therefore, we have employed one of the series of Good Clinical Practice (GCP)-compliant pharmacokinetic and safety studies that were conducted to evaluate the bioavailability and comparative bioavailability of the novel intranasal epinephrine spray relative to epinephrine injection products to investigate the mechanism of double peak. Because the two peaks are a phenomenon that appears to be speci c to injection products 7,8 and nasal epinephrine spray generally does not demonstrate two peaks, data from the nasal spray is not included in this analysis.…”

Section: Introductionmentioning

confidence: 99%

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Mechanism of the first and second peaks in epinephrine pharmacokinetics over time

Lockey,

Ellis,

Lowenthal

et al. 2023

Preprint

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Background: There is a documented double peak phenomenon following the intramuscular injection of epinephrine, however these peaks are typically representative of mean epinephrine concentrations and not individual subjects. Objective: An examination of epinephrine pharmacokinetics was conducted to explore the nature of the double peak phenomenon and to determine if the double peaks observed in mean concentration profiles were also observed in individual subjects. Methods: A GCP compliant study was conducted in 36 adult volunteers with a history of type I allergies. Blood samples were collected before and at multiple timepoints after subjects self- administered two FDA-approved epinephrine auto-injectors (EpiPen 0.3 mg and Symjepi 0.3 mg). Pharmacokinetic parameters (Cmax and tmax) and concentration-time curves were determined based on individual subjects. Subjects were categorized by their tmax (≤4 min, >4 min - ≤10 min, >10 min - ≤20 min, >20 min - ≤30 min, >30 min - ≤45 min, and >45 min, presented as ≤4 min, ≤10 min, ≤20 min, ≤30 min, ≤45 min, and >45 min, respectively). Results: The majority of individual subjects did not have double peaks. Double peaks in mean concentration-time profiles were observed when tmax was ≤4 min following EpiPen and Symjepi, tmax ≤30 min following EpiPen, and tmax ≤45 min following EpiPen. The individual epinephrine concentration curves for subjects with a tmax ≤4 min following EpiPen and Symjepi and tmax ≤45 min following EpiPen demonstrate that the majority of individual subjects do not have double peaks. Conclusion: These data suggest that the double peaks observed in mean epinephrine concentrations are likely driven by subsets of subjects with either early or late tmax values and may not necessarily be a pharmacokinetic characteristic of epinephrine.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Mechanism of the first and second peaks in epinephrine pharmacokinetics over time

Lockey,

Ellis,

Lowenthal

et al. 2023

Preprint

Self Cite

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“…Instead, their approval was based on the assumption that there were no significant differences between these injection products and the reference listed drug (IM injection with needle and syringe). However, more recent studies have established notable pharmacokinetic differences among the different autoinjector products and manual IM injection with needle and syringe [ 36 , 37 , 38 ].…”

Section: Neffy Product Informationmentioning

confidence: 99%

Development of neffy, an Epinephrine Nasal Spray, for Severe Allergic Reactions

Ellis,

Casale,

Kaliner

et al. 2024

Pharmaceutics

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Epinephrine autoinjectors (EAIs) are used for the treatment of severe allergic reactions in a community setting; however, their utility is limited by low prescription fulfillment rates, failure to carry, and failure to use due to fear of needles. Given that delayed administration of epinephrine is associated with increased morbidity/mortality, there has been a growing interest in developing needle-free, easy-to-use delivery devices. neffy (epinephrine nasal spray) consists of three Food and Drug Administration (FDA)-approved components: epinephrine, Intravail A3 (absorption enhancer), and a Unit Dose Spray (UDS). neffy’s development pathway was established in conjunction with the FDA and the European Medicines Agency and included multiple clinical trials to evaluate pharmacokinetic and pharmacodynamic responses under a variety of conditions, such as self-administration and allergic and infectious rhinitis, as well as an animal anaphylaxis model of severe hypotension, where neffy demonstrated a pharmacokinetic profile that is within the range of approved injection products and a pharmacodynamic response that is as good or better than injections. The increased pulse rate (PR) and blood pressure (BP) observed even one minute following the administration of neffy confirm the activation of α and β adrenergic receptors, which are the key components of epinephrine’s mechanism of action. The results suggest that neffy will provide a safe and effective needle-free option for the treatment of severe allergic reactions, including anaphylaxis.

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“…Intramuscular injection of epinephrine is the standard of care for the treatment of severe allergic reactions, including anaphylaxis. Epinephrine nasal spray (neffy™, ARS Pharmaceuticals, Inc., San Diego, CA, USA) is under development as a noninvasive alternative to injection for use in community settings [ 57 ]. Epinephrine nasal spray contains 0.275% DDM, which was chosen based on optimal epinephrine bioavailability in phase 1 studies [ 58 ].…”

Section: Focus On Absorption Optimizationmentioning

confidence: 99%

“…Within the context of the emerging understanding that epinephrine pharmacokinetics can vary among different injection devices, epinephrine nasal spray with DDM demonstrated a mean C max that was similar to manually injected epinephrine, with a shorter median t max . Overall, the nasal spray produced similar or more pronounced pharmacodynamic changes compared with the injected formulations [ 57 ]. Epinephrine nasal spray is currently under review with the FDA.…”

Section: Focus On Absorption Optimizationmentioning

confidence: 99%

Optimizing Absorption for Intranasal Delivery of Drugs Targeting the Central Nervous System Using Alkylsaccharide Permeation Enhancers

2023

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Intranasal delivery of drugs offers several potential benefits related to ease of delivery, rapid onset, and patient experience, which may be of particular relevance to patients with central nervous system (CNS) conditions who experience acute events. Intranasal formulations must be adapted to address anatomical and physiological characteristics of the nasal cavity, including restricted dose volume, limited surface area, and barriers to mucosal absorption, in addition to constraints on the absorption window due to mucociliary clearance. Development of an effective formulation may utilize strategies including the addition of excipients to address the physicochemical properties of the drug within the constraints of nasal delivery. Dodecyl maltoside (DDM) and tetradecyl maltoside are alkylsaccharide permeation enhancers with well-established safety profiles, and studies have demonstrated transiently improved absorption and favorable bioavailability of several compounds in preclinical and clinical trials. Dodecyl maltoside is a component of three US Food and Drug Administration (FDA)–approved intranasal medications: diazepam for the treatment of seizure cluster in epilepsy, nalmefene for the treatment of acute opioid overdose, and sumatriptan for the treatment of migraine. Another drug product with DDM as an excipient is currently under FDA review, and numerous investigational drugs are in early-stage development. Here, we review factors related to the delivery of intranasal drugs and the role of alkylsaccharide permeation enhancers in the context of approved and future intranasal formulations of drugs for CNS conditions.

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Pharmacokinetic and pharmacodynamic comparison of epinephrine, administered intranasally and intramuscularly

Cited by 20 publications

References 14 publications

Mechanism of the first and second peaks in epinephrine pharmacokinetics over time

Mechanism of the first and second peaks in epinephrine pharmacokinetics over time

Development of neffy, an Epinephrine Nasal Spray, for Severe Allergic Reactions

Optimizing Absorption for Intranasal Delivery of Drugs Targeting the Central Nervous System Using Alkylsaccharide Permeation Enhancers

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