Pharmacokinetics of adrenaline autoinjectors

Abstract

Anaphylaxis is an important medical emergency, with an estimated prevalence worldwide of 1-761 per 100 000 person-years for all causes. 1 Hospital admissions due to anaphylaxis are increasing globally; the most common triggers are foods such as peanut tree nuts and milk, wasp and bee stings and medications. 2,3 Presentations usually involve respiratory distress and/or cardiovascular collapse, but rarely result in fatal outcomes. [3][4][5][6] The mainstay of longer-term management is avoidance of the trigger. 7,8 This can be challenging, particularly for food allergy, with the issues around allergen labelling 9 which impact adversely on quality of life. 10 The evidence base for the acute management of anaphylaxis is weak, but there is a global consensus that intramuscular (IM) adrenaline is the treatment of choice. 7,8,11,12 In community settings, adrenaline can be provided for emergency use as an adrenaline autoinjector (AAI) device, 7,8 although these are not available in many countries. 13 Carrying an AAI enables IM adrenaline to be rapidly administered by the patient or a lay person. There have, however, been concerns that with some AAIs having shorter needle lengths, this could result in a subcutaneous rather than IM dose in many individuals. 14 In 2015, the Committee for Medicinal Products for Human Use (part of the European Medicines Agency) undertook a review in this area, 15 noting that a number of different factors could influence the delivery of adrenaline via an AAI: 'needle

Adrenaline auto injectors pharmacokinetic/pharmacodynamic studies and potential consequences for clinical practice

“…3,36 Additionally, based on the study conducted in ballistic gelatine, the results reveal that higher activation force with Product EP warrants F I G U R E 4 (A) C max, and (B) and max of 300 μg adrenaline injected via Product J (Jext) in the low, moderate, and high skin to muscle distance (STMD) participants. 29 higher adrenaline volume into the muscles (0.22 mL out of total 0.3 mL dose, 74.3%), compared to a lower activation force as seen in Product A (~0.08 mL out of total 0.3 mL dose, 25.7%). 3,19 Although the effects have not been tested in clinical settings, the high activation force should be considered while ensuring sufficient adrenaline delivery.…”

“…Likewise, the median T max in high STMD participants was higher than that in moderate and low STMD participants (60 vs. 12 min and ). 29 A short summary of the PK parameters administered through Product J and IM syringe is presented in Supplementary Table 5.…”

“…24 Hence, the Committee for Medicinal Products for Human Use (CHMP) recommended PK/PD studies for each AAI that are marketed in Europe to be performed by their respective Marketing Authorization Holder (MAH). 25 In this paper, the findings of the three PK/PD studies for Products A, 26 EM, 27 and EP, 28 and the PK data for Product J 29 published in a review article through a freedom of information request from Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom are analyzed. Our data will support clinicians in making evidence-based decisions, and optimal treatment effectiveness by maneuvering the inter-device functional differences in each AAI.…”

Management of IgE‐mediated food allergy in the 21st century

“…The use of adrenaline infusions has been proposed to manage refractory anaphylaxis 52 . Determinants of the pharmacokinetics of adrenaline/epinephrine autoinjectors have been investigated, but the strength of evidence is not high, due to a lack of head‐to‐head comparisons, small numbers of study participants and the failure to acknowledge the biphasic nature of intramuscular adrenaline absorption for analysis purposes 53 . To overcome the mechanical problems, as well as fears associated with needles and administration errors causing injuries 54 in the last years are emerging alternatives to the intramuscular route.…”

“… 52 Determinants of the pharmacokinetics of adrenaline/epinephrine autoinjectors have been investigated, but the strength of evidence is not high, due to a lack of head‐to‐head comparisons, small numbers of study participants and the failure to acknowledge the biphasic nature of intramuscular adrenaline absorption for analysis purposes. 53 To overcome the mechanical problems, as well as fears associated with needles and administration errors causing injuries 54 in the last years are emerging alternatives to the intramuscular route. These include intranasal, sublingual, inhaled, and needle‐free intramuscular administration of epinephrine, all of which could potentially transform our management of anaphylaxis.…”