Modeling Simulations to Predict AED Efficacy

David Blum, MD, executive medical director for neurology clinical development at Sunovion Pharmaceuticals Inc., provides a brief overview of the following poster presentation from the AAN 2016 meeting.

Utilizing pharmacokinetic-pharmacodynamic (PK-PD) modeling and simulations, researchers sought to predict the efficacy of conversion to eslicarbazepine acetate (ESL) monotherapy at 800 mg taken once daily.¹

ESL, or Aptiom, is an oral antiepileptic drug approved in the US as monotherapy or adjunctive treatment for partial-onset seizures. Conversion to ESL monotherapy at doses of 1200 mg and 1600 mg was found to be effective and well tolerated in two phase III trials, but an 800 mg dose was not studied.^2-4

Researchers used PK-PD modeling to predict efficacy outcomes in patients converting from either one or two AEDs at the 800 mg dose. Data were derived from 296 patients who participated in the two phase III studies converting to ESL as monotherapy (199 patients converted from one AED and 97 converted from two AEDs). Demographic data from this group was resampled to create 1500 virtual patients, with 500 patients simulated taking two AEDs and 1000 patients taking one AED at baseline. Similar to the dosing regimen in the phase III trials, the virtual patients were assumed to receive 400 mg ESL QD for one week, followed by 800 mg QD for 17 weeks.  

The predicted weekly eslicarbazepine minimum (minimum exposure [C_min]) and number of baseline AEDs were used to determine the probability of remaining in the trial. In the phase III trials, patients left the study if they met one or more of the predefined exit criteria indicating worsening seizure control: an episode of status epilepticus, a secondary generalized partial seizure (for patients without generalized seizures during 6 months prior to screening), two-fold increase from baseline in consecutive 28-day seizure rate, two-fold increase from baseline in consecutive two-day seizure rate, or worsening of seizures or increase in seizure frequency.

For virtual patients receiving ESL monotherapy the 90% upper prediction limits for the exit rates at 112 days were below the 65.3% threshold calculated from historical control trials. The rates were 13.5% (11.7-15.2%) for patients taking one AED at baseline and 31.3% (27.5-34.7%) for patients taking two AEDs. The probability of remaining in the trial was greater for patients converting from one previous AED and for those with higher eslicarbazepine exposure (C_min).

The model supports conversion to ESL 800 mg QD monotherapy for partial-onset seizures in adults previously taking one AED. Patients taking two AEDs were more likely to exit the study due to worsening seizures, so doses of 1200 mg or 1600 mg ESL QD should be considered, if conversion to ESL monotherapy is contemplated.

This study was supported by Sunovion Pharmaceuticals Inc.

Disclosures:

1. Sunkaraneni S, et al. Use of Pharmacokinetic-Pharmacodynamic (PK-PD) Modeling and Simulations to Predict Efficacy Outcomes with Eslicarbazepine Acetate (ESL) 800mg Once-Daily (QD) as Monotherapy Poster presentation P2.025, Apr 17, 2016. AAN Annual Meeting, Vancouver, British Columbia.

2. Sperling MR, et al. Efficacy and safety of conversion to monotherapy with eslicarbazepine acetate in adults with uncontrolled partial-onset seizures: a randomized historical-control phase III study based in North America. Epilepsia. 2015 Apr;56(4):546-555.

3. Jacobson MP, et al. Efficacy and safety of conversion to monotherapy with eslicarbazepine acetate in adults with uncontrolled partial-onset seizures: a historical-control phase III study. BMC Neurol. 2015 Mar 28;15:46.

4. Sperling MR, et al. Conversion to eslicarbazepine acetate monotherapy. A pooled analysis of 2 phase III studies. Neurology. 2016;86(12):1095-1102.