Authors :
Presenting Author: Dan Chiche, MD – CrossJect
Olivier Lacombe, PhD – CrossJect
Nathalie Loughraieb, BS – CrossJect
Corentin Mit, PhD – PhInc Development
Virginie Gualano, PhD – PhInc Development
Rationale:
ZEPIZURE® (ZENEO® Midazolam) is under development for the emergency treatment of Status Epilepticus (SE). As ZENEO® is a needle free device for intramuscular (IM) injection, depth of injection should be assessed by Magnetic Resonance Imaging (MRI). Targeted injection site is thigh. ZENEO® is designed to be used as rescue medication in emergency situations where access to bare skin may be limited, justifying a studying performance of the device also through clothing. In addition, because of the needle free drug solution penetration and inter-individual anatomical variability, the impact of IM fraction vs subcutaneous (SC) fraction on exposure should be estimated.Methods:
50 healthy volunteers were randomized (crossover design) to receive ZENEO® saline (device loaded with 0.625 mL saline mimicking midazolam solution) applies on the thigh directly on bare skin or through clothing. MRI was performed between 10- and 20-minutes post injections.
A physiologically based pharmacokinetic (PBPK) modeling, using GastroPlus™ (G+) to assess 10 mg midazolam exposure with various drug solution fractions in IM/SC injection.
Results:
The Table below summarizes the main results of the MRI study. Most volunteers had successful IM injections and maximal vertical length exceed the regular 1 inch needle length.
The Figure below shows the impact on “time to maximum concentration” (Tmax), “maximum blood concentration” (Cmax), and “Area Under the Curve” (AUC) of various fractions of injected dose from 100% IM (Ref.) to 100% SC.
Even in the worst-case scenario with 100% SC injection, the impact on key parameters of exposure is limited: minor reduction in Cmax and no impact on the Tmax and AUC.
Conclusions:
ZENEO® is expected to deliver midazolam IM in most patients, in emergency situation, on thigh either on bare skin or through clothing. While the IM injection has been demonstrated, a mixed IM/SC dosing has negligible impact on midazolam pharmacokinetics.
This analysis indicates that ZEPIZURE® features are consistent with its use in SE in emergency situation, with benefits of midazolam intramuscular injection while variations in the IM/SC fraction are very unlikely to be associated with a clinically relevant impact on safety or efficacy.
Funding: Funded by CrossJect