ESETT Pharmacokinetic-Pharmacodynamic Study

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Status epilepticus (SE) is a common neurological emergency associated with high morbidity and mortality. While benzodiazepines are an effective first-line therapy for many patients with SE, evidence is lacking to guide treatment when drugs in this group fail. The Established Status Epilepticus Treatment Trial (ESETT), which is underway, is a randomized, blinded, response-adaptive study whose objective is to identify the most effective treatment for children and adults with convulsive SE refractory to standard dose of a benzodiazepine defined as established SE (ESE). ESETT is comparing three drugs: fosphenytoin (FOS), valproic acid (VPA), and levetiracetam (LVT). The primary outcome is clinical cessation of status epilepticus, determined by the absence of clinically apparent seizures and improving responsiveness, at 60 minutes after the start of study drug infusion, without the use of additional anti-seizure medications. However, the pharmacokinetics and pharmacodynamics of these three drugs, when used for ESE, are poorly understood. ESETT offers a unique opportunity to investigate drug exposure-response relationships. The specific aim of this ancillary study is to relate drug exposure (partial area under the curve, pAUC, from time 0 to 60 min after start of drug infusion) with the ESETT primary outcome and key secondary outcomes measures. The following hypotheses will be tested: Hypothesis 1: Patients with higher drug exposures (pAUC based on unbound or total plasma concentrations of FOS, VPA and LEV) will more likely respond to treatment. Hypothesis 2: Patients with higher drug exposures (pAUC) will have a higher incidence of adverse effects commonly associated with the study drugs. Hypothesis 3: The relationship between drug exposure and response will differ by gender, age group, and weight or BMI. While ESETT will identify the most or least effective clinical choice overall, this ancillary study will elucidate reasons for response and non-response. Further, an understanding of the exposure-response relationships will allow evidence-based guidance on how best to use these medications in patient care. Lastly, information from this ancillary study can guide future clinical trials as new agents are tested against the best drug or drugs that is/are ultimately determined by ESETT. Thus, this study will impact clinical practice and future ESE investigations.