PHARMACOKINETICS STUDY OF EPINEPHRINE SUBLINGUAL FILM: RESULTS FROM THE FORMULATION AND DOSAGE SELECTION

Abstract

<h3>Introduction</h3> We have previously published the results from a first in human study that identified a prototype producing pharmacokinetics (PK) and pharmacodynamics (PD) of a sublingual film using a novel prodrug epinephrine (DESF). Three commercially viable formulations, across two dosage strengths each, are explored to establish a bridge to the lead formulation identified in a previous first in human study. <h3>Methods</h3> EPIPHAST is a randomized, open-label, three-part adaptive design, crossover study in healthy adult subjects comparing the PK and PD of DESF. In its Phase 1, multiple oral film formulations and dosage strengths of DESF were evaluated to identify an intended final formulation. Sixteen healthy volunteers were selected for each formulation and dosage, or a 0.5 mg IM injection of epinephrine for comparison. <h3>Results</h3> Seven different configurations were examined, and PK parameters were measured. The two best formulations of DESF (Formulation 5: 10 mg and 12 mg) rapidly reached clinically meaningful blood concentrations, with a median Tmax of 15 minutes and 22.5 minutes, respectively. Mean Cmax values were 285pg/mL and 268pg/mL for the two configurations, respectively. Formulation 5 at 12 mg produced results most comparable to both the first in human study as well as those reported for IM injections of epinephrine. The adverse event profiles and tolerability were similar across all formulations and dosage strengths. <h3>Conclusion</h3> The findings show that DESF formulations can deliver sufficient blood concentrations of epinephrine sooner than that observed with the higher dose of IM epinephrine injection in line with existing epinephrine autoinjectors and without concerns for safety or tolerability.