(979) Perampanel Plasma Concentrations and Clinical Effects Following 4 mg/day Monotherapy in Patients with Partial-Onset Seizures (POS): Post Hoc Analysis of Study 342 (FREEDOM)
Professor, Department of Experimental and Clinical Pharmacology University of Minnesota, Minneapolis, MN, USA
Rationale: In the U.S. and Japan, perampanel is approved for POS (adjunctive and monotherapy) in patients aged ≥ 4 years, and adjunctive treatment of primary generalized tonic-clonic seizures in patients aged ≥ 12 years. FREEDOM (NCT03201900) is a multicenter, open-label Phase III study of perampanel monotherapy in patients (aged 12–74 years) with newly diagnosed/currently untreated recurrent POS, with/without secondarily generalized seizures. We explore whether perampanel plasma concentrations are associated with clinical efficacy/tolerability following perampanel 4 mg/day monotherapy. Methods: The Core Study comprised 4-week Pretreatment and 32-week Treatment (6-week Titration; 26-week Maintenance) Phases; patients received perampanel 4 mg/day, with titration up to 8 mg/day in case of seizure. Blood samples for pharmacokinetic (PK) assessments were collected during study visit (anytime postdose) at the end of Titration Period (Week 6) and during the 4-mg Maintenance Period (Weeks 10 and 20). Perampanel plasma concentrations at Week 6 are summarized in the modified Intent-to-Treat population (mITT; patients in the 4-mg Maintenance Period with ≥ 1 post-dose efficacy assessment), stratified by seizure-free status and with/without treatment-emergent adverse events (TEAEs) during the 4-mg Maintenance Period. Results: Overall, 73/89 patients treated during the Core Study entered the 4-mg Maintenance Period (mITT) and 16 discontinued (TEAEs, consent withdrawn, inadequate therapeutic effect). PK data were available for 68 patients. The mean (standard deviation [SD]; range) perampanel plasma concentration at Week 6 was 392.8 (215.5; 0.5 to 893.0) ng/mL in the 44 seizure-free patients receiving perampanel 4 mg/day vs 331.2 (141.2; 67.0 to 695.0) ng/mL in 24 non–seizure-free patients (P=0.1608 [2-tailed t-test]). There was a large intersubject variability in perampanel plasma concentrations with a wide overlap between seizure-free and non–seizure-free patients and no clear association between perampanel concentrations and treatment outcome (Figure 1). There was also a wide overlap of perampanel levels in patients with (n=30) or without (n=38) TEAEs during the 4-mg Maintenance Period with no clear association between perampanel plasma concentrations and incidences of overall TEAEs, related TEAEs, or the most common TEAEs associated with perampanel (Figure 2). Conclusions: Although most patients receiving 4 mg/day perampanel monotherapy achieved seizure freedom, there was no clear association between perampanel plasma levels and seizure control nor occurrence of TEAEs, suggesting that dosing should be individualized and based on clinical efficacy and/or tolerability. Funding: Please list any funding that was received in support of this abstract.:
