Abstract
Timely and proper injection of epinephrine is critical to prevent serious consequences relating to anaphylaxis. In a recent bioavailability study comparing epinephrine delivery from the Auvi-Q™ and EpiPen® epinephrine autoinjectors, the Auvi-Q failed to meet the bioequivalence threshold when using partial area under the curve (AUC) analyses based on zero to Tmax recommended for highly variable drugs such as epinephrine. Peak plasma epinephrine concentrations for the EpiPen occurred 10 minutes (median Tmax) after dosing, while peak concentrations for the Auvi-Q occurred 20 minutes after dosing. Though bioequivalence may be concluded for Cmax, AUCinf, and AUC0–t, for fast-acting therapeutics used to treat life-threatening conditions, such as epinephrine, additional pharmacokinetic parameters such as AUC zero to Tmax may be important to evaluate when assessing bioequivalence.
Anaphylaxis is a rapid-onset allergic reaction that can be life threatening, and its rate of occurrence is increasing, especially in younger people.Citation1,Citation2 Though the financial impact of anaphylaxis can be difficult to determine, since this condition is likely underreported and underdiagnosed,Citation2,Citation3 the economic burden of anaphylaxis in the United States was estimated in 2010 at US$1.2 billion in direct expenditures.Citation4 As anaphylactic reactions often occur in community settings without ready access to a health care professional, the World Health Organization and all published national (US) guidelines list epinephrine as the only first-line option for the initial treatment of anaphylaxis.Citation1 Epinephrine acts to prevent and relieve upper-airway obstruction and alleviate shock. Intramuscular injection into the thigh is a recommended route of administration,Citation5 and epinephrine autoinjectors are the primary component of emergency preparedness for anaphylaxis.Citation1 Timely and proper injection of epinephrine is critical to prevent serious consequences such as hospitalizations or death.Citation1 Fatalities from anaphylaxis can occur in a time frame ranging from 5 to 30 minutes depending on the type of allergen exposure.Citation6 Considering the importance of rapid absorption of epinephrine, how best should the delivery of epinephrine be evaluated when assessing the bioequivalence (BE) of a new autoinjector device?
The US Food and Drug Administration (FDA) reviewed the bioavailability of epinephrine from the Auvi-Q™ autoinjector (Sanofi, Bridgewater, NJ, USA) compared with that of the EpiPen® autoinjector. This assessment was based on study INT0802, a randomized, single-dose, single-blind, two-treatment, crossover study to document the bioavailability of epinephrine delivered by Auvi-Q and EpiPen.Citation7,Citation8 The study design and analysis used the scaled BE approach by Haidar et al,Citation9 which is currently recommended by the FDA for high-variability substances such as epinephrine (ie, intrasubject variability > 30%). Seventy-one individuals were included in the pharmacokinetic (PK) data analysis; 67 individuals received dosing with Auvi-Q, while 69 subjects received at least one dose using the EpiPen.
The primary PK parameters for BE assessment were peak drug concentration (Cmax) and area under the curve (AUC); baseline correction was performed to adjust for endogenous levels of epinephrine. Secondary partial AUC parameters were also determined for each individual’s concentration–time profiles by calculating the AUC from time zero to the time of the maximum plasma concentration (Tmax) after injection with the EpiPen. Partial AUC values were higher for the EpiPen than for the Auvi-Q. As shown in , BE may be concluded for Cmax and concentration–time curve from baseline to the last measurable concentration (AUC0–t) and AUC from baseline extrapolated to infinity (AUCinf). However, BE was not concluded for the partial AUC analyses based on zero to Tmax of reference after first administration (R1ACOTMX) or based on zero to Tmax of reference after second administration (R2ACOTMX).
Table 1 Baseline corrected results for comparison of Auvi-Q™ (Sanofi, Bridgewater, NJ, USA) to EpiPen® (Mylan Specialty LP, Basking Ridge, NJ, USA) autoinjectors
Further, based on median Tmax parameters, peak epinephrine concentrations for EpiPen occurred 10 minutes after dosing (0.170 hours, range 0.07–1.00) while peak concentrations for Auvi-Q occurred 20 minutes after dosing (0.330 hours, range 0.08–1.00). While this difference was not considered significant, a numeric Tmax difference may be highly critical to the therapeutic efficacy of epinephrine administration.
The PK parameters Cmax, AUC0–t, and AUCinf for Auvi-Q and EpiPen, which met the equivalence criteria using the baseline-corrected data set, were presented by Edwards et al at the American Academy of Allergy, Asthma, and Immunology annual meeting.Citation10 This presentation did not specifically comment on partial AUC analyses, which failed to meet the BE threshold.Citation10 However, given the clinical significance of rapid epinephrine delivery, additional PK parameters such as Tmax and partial AUC analysis may be considered as a requirement for BE. When there is a need for rapid absorption of a life-saving medication, in the case of fast-acting, highly variable therapeutics, additional PK factors might be important to evaluate when assessing BE.
Acknowledgment
Editorial support was provided by Rebecca E Slager, PhD, MS, at MedThink SciCom.
Disclosure
Editorial support was funded by Mylan Specialty LP (Basking Ridge, NJ, USA). Dr Sclar has served as a consultant to Mylan Specialty LP.
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