Epinephrine in Anaphylaxis: Preclinical Study of Pharmacokinetics after Sublingual Administration of Taste-Masked Tablets for Potential Pediatric Use

Ousama Rachid,Mutasem Rawas-Qalaji,Keith Simons

doi:10.3390/pharmaceutics10010024

Ousama Rachid, Mutasem Rawas-Qalaji + Show 1 more

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https://doi.org/10.3390/pharmaceutics10010024

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Abstract

Epinephrine is a life-saving treatment in anaphylaxis. In community settings, a first-aid dose of epinephrine is injected from an auto-injector (EAI). Needle phobia highly contributes to EAI underuse, leading to fatalities—especially in children. A novel rapidly-disintegrating sublingual tablet (RDST) of epinephrine was developed in our laboratory as a potential alternative dosage form. The aim of this study was to evaluate the sublingual bioavailability of epinephrine 30 mg as a potential pediatric dose incorporated in our novel taste-masked RDST in comparison with intramuscular (IM) epinephrine 0.15 mg from EAI, the recommended and only available dosage form for children in community settings. We studied the rate and extent of epinephrine absorption in our validated rabbit model (n = 5) using a cross-over design. The positive control was IM epinephrine 0.15 mg from an EpiPen Jr®. The negative control was a placebo RDST. Tablets were placed under the tongue for 2 min. Blood samples were collected at frequent intervals and epinephrine concentrations were measured using HPLC with electrochemical detection. The mean ± SEM maximum plasma concentration (Cmax) of 16.7 ± 1.9 ng/mL at peak time (Tmax) of 21 min after sublingual epinephrine 30 mg did not differ significantly (p > 0.05) from the Cmax of 18.8 ± 1.9 ng/mL at a Tmax of 36 min after IM epinephrine 0.15 mg. The Cmax of both doses was significantly higher than the Cmax of 7.5 ± 1.7 ng/mL of endogenous epinephrine after placebo. These taste-masked RDSTs containing a 30 mg dose of epinephrine have the potential to be used as an easy-to-carry, palatable, non-invasive treatment for anaphylactic episodes for children in community settings.

Highlights

Prompt injection of epinephrine in the mid-outer thigh using an auto-injector is the recommended first-aid treatment of anaphylaxis in community settings [1]
102.97 ± 8.28 a AV, USP acceptance value; b DD (%), Percentage of drug dissolved in the first 120 s
The plasma concentration of epinephrine versus time profiles following the administration of placebo and epinephrine 30 mg sublingual tablets, and epinephrine 0.15 mg by intramuscular injection are presented in Figure 1 as means ± SEM

Summary

Introduction

Prompt injection of epinephrine in the mid-outer thigh (vastus lateralis muscle) using an auto-injector is the recommended first-aid treatment of anaphylaxis in community settings [1]. Many patients and caregivers who have an epinephrine auto-injector available were reported to delay injecting epinephrine because of their fear of needles [3,4,5]. There is an increasingly challenging availability and affordability issue of epinephrine autoinjectors worldwide, with pharmacy acquisition costs in North America ranging from $170 to $430 US dollars per pack [6]. This is compounded by the need for multiple devices to be placed in various locations as part of the user’s preparedness plan, such as home, work, school, and during traveling; and the need to replace expired devices almost every year. Manual techniques of removing and administering second or third epinephrine doses from used devices and filling or prefilling injections from epinephrine ampules have been suggested to overcome the high cost of autoinjectors; the accuracy, safety, and practicality of these techniques are questionable [7,8,9,10]

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