Prediction of efficacy for conversion from adjunctive therapy to monotherapy with eslicarbazepine acetate 800 mg once daily for partial-onset epilepsy

Soujanya Sunkaraneni; Julie A Passarell; Elizabeth A Ludwig; Jill Fiedler-Kelly; Janet K Pitner; Todd A Grinnell; David Blum

doi:10.2147/CPAA.S133815

Prediction of efficacy for conversion from adjunctive therapy to monotherapy with eslicarbazepine acetate 800 mg once daily for partial-onset epilepsy

Clin Pharmacol. 2017 Jun 27:9:65-72. doi: 10.2147/CPAA.S133815. eCollection 2017.

Authors

Soujanya Sunkaraneni¹, Julie A Passarell², Elizabeth A Ludwig², Jill Fiedler-Kelly², Janet K Pitner¹, Todd A Grinnell¹, David Blum¹

Affiliations

¹ Sunovion Pharmaceuticals Inc., Marlborough, MA, USA.
² Cognigen Corporation (a SimulationsPlus company), Buffalo, NY, USA.

Abstract

Purpose: Eslicarbazepine acetate (ESL) is a once-daily (QD) oral antiepileptic drug (AED) indicated for partial-onset seizures (POS). Clinical studies of gradual conversion to ESL 1,200 and 1,600 mg QD monotherapies were previously conducted in patients with POS who were not well-controlled by 1 or 2 AEDs. This report describes modeling and simulation of plasma eslicarbazepine (primary active metabolite of 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 POS.

Patients and methods: A previously developed population pharmacokinetic model for ESL monotherapy was used to predict minimum plasma eslicarbazepine concentration (C_min) 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400 mg QD for 1 week, followed by 800 mg QD for 17 weeks (similar to ESL monotherapy trials where the other AEDs were withdrawn during the first 6 weeks following titration to the randomized ESL dose). Model-predicted C_min as a time-varying covariate and number of baseline AEDs were used 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. A previously developed extended Cox proportional hazards exposure-response model was used to relate time-varying eslicarbazepine exposure to the time to study exit.

Results: For virtual patients receiving ESL monotherapy (800 mg QD), 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.

Conclusion: This model-based assessment supports conversion to ESL 800 mg QD monotherapy for POS in adults taking 1 AED. For patients taking 2 concomitant AEDs, however, prescribers should consider maintenance doses of 1,200 or 1,600 mg ESL QD to reduce the likelihood of seizure worsening if conversion to ESL monotherapy is contemplated.

Keywords: antiepileptic; eslicarbazepine; monotherapy; simulations.