Abstracts

Rationale: A fundamental principle of pharmacology is that response is related to drug exposure at the site of action. Exposure in turn, is determined by dose and patient-specific variables that can include weight. The Established Status Epilepticus Treatment Trial (ESETT) was a multi-center, randomized, double-blind study comparing fosphenytoin (FOS), levetiracetam (LEV) and valproic acid (VPA) in patients with benzodiazepine-refractory status epilepticus (SE). The primary outcome of the study was cessation of SE as determined by absence of clinically apparent seizures 60 minutes after the start of study drug infusion without use of additional anti-seizure medication. Weight-based dosing was employed for ESETT drugs and doses were capped at 75 kg due to safety considerations. We hypothesized that the odds of treatment failure were higher in adults (>= 18 years) weighing > 75 kg as they received a lower dose in mg/kg. The objective of this work was to evaluate the effect of weight, dose/weight, and sex on seizure cessation. Methods: Data from all 249 adults enrolled in ESETT were used for these analyses. The volume of drug administered could not be determined for 2 participants and were excluded from the analyses. Clinical cessation of SE was expressed in a binary form (0=treatment failure, 1=treatment success) and used as the dependent variable in logistic regression models. The following outcome predictors were evaluated: weight (<= or > 75 kg and <= or > 90 kg), treatment (FOS, VPA or LEV), sex (F/M), and weight-normalized dose. Significance was determined as an alpha level < 0.05. Results: Weights were normally distributed ranging from 36-157 kg and centered at ~75 kg (Figure 1). Of the 247 subjects, 122 (~50%) weighed > 75 kg and received the capped dose of ESETT drug. The overall success rate of seizure termination was ~43% in those < 75 kg vs. ~39% in those >75 kg.A logistic regression model for the primary outcome vs. weight showed that the odds of success were 10.3% lower for those >75 kg and 14.3% lower for those > 90 kg, but these differences were not significant (p=0.6). Nor were there any significant interactions when the logistic model included treatment and gender. The FOS, LEV, VPA response rates for those > 75kg were 2.5%, 2.5%, and 15% lower than for those <= 75kg, respectively. Further, there was not significant difference in response rates for any of the drugs based on the individual logistic models using dose/weight as the primary predictor.  Conclusions: In ESETT weight-based dosing with a 75 kg cut-off did not appear to have an effect on seizure cessation. This suggests that the doses used in the trial resulted in drug concentrations above that needed for therapeutic outcome even in those >