Pharmacokinetic Modeling of Optimized Midazolam and Pentobarbital Dosing Used in Treatment Protocols of Refractory Status Epilepticus

OBJECTIVES:To model bolus dosing, infusion rate, and weaning rate on theoretical serum concentration of midazolam and pentobarbital used in the treatment of refractory status epilepticus (RSE). DESIGN:One- and two-compartment in silico pharmacokinetic models of midazolam and pentobarbital. SETTING:Not applicable. SUBJECTS:Not applicable. INTERVENTIONS:We compared the model variables used in midazolam and pentobarbital protocols for standard RSE. MEASUREMENTS AND MAIN RESULTS:Standard RSE treatment protocols result in steady-state serum concentrations that are 6.2-9.0-fold higher for the one-compartment model and 2.3-4.7-fold higher for the two-compartment model. In the model, not including bolus doses delays the achievement of serum steady-state concentration by 0.5 and 2.7 hours for midazolam and pentobarbital, respectively. Abrupt discontinuation of these medications reduces modeled medication exposure by 1.1 and 6.4 hours, respectively. CONCLUSIONS:Our in silico pharmacokinetic modeling of standard midazolam and pentobarbital dosing protocols for RSE suggests potential variables to optimize in future clinical studies.

Automated summary

In silico pharmacokinetic modeling of midazolam and pentobarbital suggests that standard treatment protocols for refractory status epilepticus result in higher steady-state serum concentrations. Not including bolus doses delays the achievement of steady-state concentration, while abrupt discontinuation reduces medication exposure. These models provide potential variables to optimize in future clinical studies.