Estimation of the Intramuscular Dose of Midazolam in Mice to Achieve the Therapeutic Plasma Concentration Effective for the Treatment of Status Epilepticus in Humans
Abstract number :
1.135
Submission category :
2. Translational Research / 2E. Other
Year :
2021
Submission ID :
1825667
Source :
www.aesnet.org
Presentation date :
12/4/2021 12:00:00 PM
Published date :
Nov 22, 2021, 06:44 AM
Authors :
Dorota Zolkowska, PhD - Department of Neurology, School of Medicine, University of California, Davis, Sacramento, CA, USA 95817; Chun-Yi Wu, PhD - Assistant Project Scientist, Department of Neurology and Bioanalysis and Pharmacokinetics Core Facility, School of Medicine, University of California, Davis, Sacramento, CA, 95817; Colleen Stone, BS - Staff Research Associate, Department of Neurology, School of Medicine, University of California, Davis, Sacramento, CA, USA 95817; Michael Rogawski, MD, PhD - Professor of Neurology and Pharmacology, Department of Neurology, School of Medicine, University of California, Davis, Sacramento, CA, USA 95817
Rationale: Convulsive status epilepticus (SE) is a neurologic emergency associated with mortality ranging from 3% to 40%. Intramuscular (IM) midazolam HCl (MDZ) has been demonstrated to be an effective treatment for SE. A formulation of MDZ (Seizalam®) was recently approved by the FDA for the treatment of SE in adults. Although MDZ is a standard of care initial therapy for SE, it often fails to control seizures, especially when there is a prolonged delay to treatment. There is therefore a need for follow-on therapies that can be administered if MDZ fails. According to the prescribing information, the recommended human dose of 10 mg achieves a plasma Cmax of 113.9 ± 30.9 (SD) ng/mL. The objective of the present study was to estimate the IM dose of MDZ which when administered to mice yields a Cmax equal to the human value. The human equivalent dose estimate is required in studies exploring novel SE treatments administered in conjunction with midazolam. We utilized 2-compartment PK modeling and simulation to estimate the required dose in mice. Our analysis assumes that Cmax is the appropriate PK parameter to match; we did not attempt to match other parameters such as AUC.
Methods: Mice received a 1.8 mg/kg IM injection of MDZ. Trunk blood samples were collected at intervals in chilled tubes with K2EDTA. The plasma was separated and MDZ levels were measured using LC-MS/MS (LLOQ for MDZ=50 pg/mL). Non-compartmental analysis (NCA) was performed to find Tmax, Cmax, and AUC of the dataset. The concentration-time data was also fitted with 2-compartment PK model to estimate the PK parameters, including Ka, V, V2, CL, and CL2. These PK parameter estimates were used for the PK simulation to find the dose associated with the target Cmax.
Results: NCA provided estimates of Tmax=0.5 min, Cmax=1059.36 ng/mL, and AUClast(360min)=19632.14 min*ng/mL. A PK simulation was performed using the parameter estimates from the 2-compartment PK model to determine the scale factor between input dose and Cmax. Based on the model, the Cmax for a 1.8 mg/kg dose is 874.74 ng/mL. By linear scaling, the dose to achieve the targeted Cmax is 0.23 mg/kg.
Conclusions: In conclusion, our PK modeling and simulation indicates that an IM MDZ dose of 0.23 mg/kg mice is expected to yield the same plasma Cmax value as obtained with a 10 mg dose of Seizalam® in humans. Therefore, this dose is proposed to be applied in mouse SE models to mimic the human dosing.
Funding: Please list any funding that was received in support of this abstract.: NINDS grant #1U54NS079202, DZ, MAR.
Translational Research