Sunkaraneni S, et al. – The authors conducted this study to describe modeling and simulation of plasma eslicarbazepine (primary active metabolite of eslicarbazepine acetate (ESL)) concentrations and time to monotherapy study exit to predict efficacy for conversion to ESL monotherapy at a lower dose of 800 mg, as an option for patients requiring or not tolerating higher doses since this regimen is effective in adjunctive therapy for partial–onset seizures (POS). In adults taking 1 antiepileptic drug (AED), this model–based assessment supported conversion to ESL 800 mg once–daily (QD) monotherapy for POS. However, for patients taking 2 concomitant AEDs, prescribers had to consider maintenance doses of 1,200 or 1,600 mg ESL QD to reduce the likelihood of seizure worsening if conversion to ESL monotherapy was contemplated.

• The authors used a previously developed population pharmacokinetic model for ESL monotherapy to predict minimum plasma eslicarbazepine concentration (Cmin) in 1,500 virtual patients taking 1 (n=1,000) or 2 (n=500) AEDs at baseline, treated with ESL 400 mg QD for 1 week, followed by 800 mg QD for 17 weeks (similar to ESL monotherapy trials where the other AEDs were withdrawn during the first 6 weeks following titration to the randomized ESL dose).
• They used model-predicted C_min as a time-varying covariate and number of baseline AEDs to determine the weekly probability of each patient meeting exit criteria (65.3% threshold) indicative of worsening seizure control in 500 simulated ESL monotherapy trials.
• They used a previously developed extended Cox proportional hazards exposure–response model to relate time-varying eslicarbazepine exposure to the time to study exit.

• The 95% upper prediction limit for exit rate at 112 days of 34.9% in patients taking 1 AED at baseline was well below the 65.3% threshold from historical control trials, while the estimate for patients taking 2 AEDs (70.6%) was slightly above the historical control threshold for virtual patients receiving ESL monotherapy (800 mg QD).