Abstracts

Rationale: Perampanel is a novel AMPA antagonist, in development for epilepsy by Eisai Inc. A worldwide development program is needed to understand and prescribe new drugs appropriately. Broad patient demographics, including full representation of concomitant AEDs are needed. It is important to consider PK/PD and dose/response data on perampanel co-administered with CYP3A4 inducing/non-inducing AEDs, obtained from Phase II trials, to select appropriate doses toward optimally designed Phase III trials. Two identical, randomized, placebo-controlled Phase III trials have been undertaken (EXPLORE 304 and 305) to assess safety and efficacy of perampanel (8mg, 12mg) in patients with treatment-resistant partial-onset seizures. Pop-PK and exposure-response are evaluated with the sparse PK sampling approach to plasma concentrations of perampanel and concomitant AEDs. These trials are being conducted in different regions of the world. Methods: As of May 2010, EXPLORE 305 had enrolled 315/449 (70%) patients from 78 sites in Europe/Israel, the United States, India/S. Africa (after screen failures and early terminations). EXPLORE 304 had similarly enrolled 364/534 (68%) patients from 77 sites in S. America/Mexico, and N. America. Patient characteristics including age, gender, number of background AEDs (1, 2 or 3), and use of hepatic enzyme-inducing AEDs at baseline were compared among subjects for different regions and countries. Only countries randomizing >20 subjects were used for individual country assessment. Type of AED was evaluated using an earlier and smaller clinical dataset (EXPLORE 305 n=271; EXPLORE 304 n=310). Results: Age and gender of subjects did not differ by region, but race varied regionally mainly in percentages of Caucasians and Asians. Mean number of background AEDs among subjects in different countries was similar, from 2.0 (Mexico, Chile) to 2.5 (Israel). Use of a single background AED ranged from 4-5% (Canada, Israel) to 21% (Mexico). Only in Israel were most subjects (59%) on 3 AEDs. Regional use of inducers as background AEDs averaged 58% but varied. Use of the 4 older AEDs: carbamazepine (CBZ), phenytoin (PHT), phenobarbital (PB) and valproic acid (VAL) was higher in S. America/Mexico and India/S. Africa, and lower in N. America and Europe/Israel (see table). Conversely, the newer AEDs lamotrigine (LTG) and levetiracetam (LEV) were used more in N. America and Europe/Israel. Conclusions: The global perampanel Phase III program was based on Phase II results in subjects exposed to a broad range of doses and concomitant inducer/non-inducer AEDs. PK/PD analysis and dose/response outcome were used to conclude that no dose adjustments would be needed to assess efficacy outcomes and to select appropriate doses for Phase III. The Phase III program, with broad demographic representation of subjects on a full range of concomitant inducer/non-inducer AEDs, with the differences shown here in background AEDs across regions, will allow assessment of PK/PD interactions, which is helpful for accurate and useful prescribing information. (Support: Eisai Inc.)