Authors :
Presenting Author: Adeboye Bamgboye, BPharm – University of Minnesota
Eric Rosenthal, MD – Medical Director, MGH Neurosciences Intensive Care Unit, Massachusetts General Hospital; James Cloyd, PharmD – Professor and Director, Experimental and Clinical Pharmacology and Center for Orphan Drug Research, University of Minnesota; Jaideep Kapur, MBBS PhD – Professor, Neuroscience and Neurology, University of Virginia; Robert Silbergleit, MD – Professor, Emergency Medicine, University of Michigan; James Chamberlain, MD – Division Chief, Emergency Medicine, Children's National Hospital; Shahriar Zehtabchi, MD – Professor, Emergency Medicine, Downstate Health Sciences University; Thomas Bleck, MD – Professor, Neurology, Northwestern University; Mark Quigg, MD – Professor, Neurology, University of Virginia; Shlomo Shinnar, MD,PhD – Professor, Neurology and Pediatrics, Albert Einstein College of Medicine; Lisa Coles, PhD – Research Assistant Professor and Associate Director, Experimental and Clinical Pharmacology and Center for Orphan Drug Research, University of Minnesota
Rationale:
Status epilepticus (SE) is a life-threatening emergency requiring urgent intervention. Benzodiazepines are the first-line treatment but are not always effective. Treatment options for patients with SE refractory to benzodiazepines, known as established status epilepticus (ESE), include phenytoin/fosphenytoin, levetiracetam, and valproate, which are only effective in about 50% of patients. Ketamine is a promising add-on option for ESE, given its ability to terminate SE in preclinical animal models, its use in super-refractory SE, and its long-standing clinical use for other conditions. A proposed study, Ketamine add-on therapy for Established Status Epilepticus Treatment Trial (KESETT), aims to investigate whether ketamine, added to levetiracetam, is superior to levetiracetam alone for ESE. Additionally, KESETT provides an opportunity to examine the relationship between ketamine plasma concentrations and response. Pharmacokinetic simulations are useful to select doses and identify optimal sampling times in constrained emergency environments. Furthermore, simulation results are critical in investigating concentration-response relationships. This work aimed to simulate concentration-time profiles for the doses selected in KESETT and, using this information, identify optimal pharmacokinetic sampling windows for blood collection.Methods:
Individual concentration-time profiles were simulated for various ketamine doses and infusion times using population pharmacokinetic parameters reported from literature. The weight-based dosing used in the simulations was adapted from The Established Status Epilepticus Treatment Trial and capped at 75kg. Adult and child weights were sampled from a normal distribution (mean 75kg, SD 20kg and mean 20kg,SD 10kg respectively). The criteria for dose selection was obtaining concentrations related to efficacy while minimizing concentrations associated with anesthesia. Ketamine concentrations were simulated (n=400) for doses ranging from 1mg/kg to 4mg/kg. Non-compartmental analysis was used to estimate the partial area under the curve from 0-2 hours (pAUC), a measure of early drug exposure. Optimal pharmacokinetic sampling times were determined using PopED Lite (Version 2.13). The number of samples were constrained between two and four to be collected within twenty minutes and four hours post-start of infusion.Results:
Doses of 1mg/kg and 3mg/kg were selected. Fig.1 shows pAUCs ranging from 0.1 to 4 µg∙hr/mL. The optimal sampling times identified were 25, 29, 31, and 106 mins. These were regrouped into windows of 20-40 mins and 90-120 mins and, if feasible, one additional window at 40-90 mins post start of infusion.Conclusions:
A rational approach utilizing simulation, identified optimal doses of 1 and 3mg/kg for a ketamine treatment trial for ESE and optimal pharmacokinetic sampling windows. Simulations of the specified doses show a wide range of concentrations, increasing the likelihood of successfully relating drug exposure and response.
Funding: N/A