Abstracts

Rationale: Perampanel (PER) is a selective, noncompetitive AMPA-antagonist approved as adjunctive treatment for partial-onset seizures. PER is the first approved drug in the novel pharmacologic class of AMPA-glutamate antagonists. To address potential for abuse of PER, 2 studies, designed according to current abuse liability guidelines, were conducted in recreational polydrug users.Methods: Study 1: double-blind (DB), ascending single-dose exploratory study of PER in 56 adults with history of psychedelic drug use and use of CNS depressants, opiates, stimulants or cannabinoids. Subjects were randomly assigned to 1 of 4 treatment groups (PER or placebo): 8 then 16mg; 12 then 20mg; 24 then 32mg; 28 then 36mg. Study 2: 40 adults with history of psychedelic drug and CNS depressant use included. Subjects received single oral dose treatments in randomized, DB, crossover manner (1 at each treatment period), of PER(8, 24 & 36mg), Schedule IV alprazolam(1.5 & 3mg), Schedule III ketamine(100mg) and placebo. Each subject had 10 treatment periods (6 active; 1 randomized placebo; 3 washout placebos). Primary pharmacodynamic (PD) endpoints included positive effects (Addiction Research Center Inventory [ARCI] Morphine Benzedrine Group [MBG] scale), balance of effects (Drug Liking Visual Analog Scale [VAS] and Subjective Drug Value [SDV]) and sedative effects (ARCI Pentobarbital Chlorpromazine Alcohol Group [PCAG] scale). Secondary endpoints included Bad Drug Effects, Overall Drug Liking and Take Drug Again VASs.Results: Study 1 exploratory results provided the basis for selection of Study 2 doses. Table 1 shows Study 2 primary PD results. Alprazolam doses and ketamine were each associated with higher positive and balance peak effects (maximum effect, Emax) compared to placebo (p 0.001), confirming study validity. All PER doses were associated with higher positive, balance and sedative effects (Emax) compared to placebo (p<0.01 for 8mg; p<0.001 for 24 & 36mg). PER therapeutic dose (8mg) was associated with lower ARCI MBG, SDV and ARCI PCAG Emax compared to alprazolam doses (p<0.05) and lower ACRI MBG, Drug Liking VAS and SDV Emax compared to ketamine (p<0.001). Compared to alprazolam doses, PER 24 & 36mg doses were not statistically different on primary endpoints. Secondary endpoints showed greater Bad Drug Effects Emax (p<0.01 except PER 24mg vs alprazolam 3mg) but lower Overall Drug Liking and Take Drug Again VASs (p=ns). Compared to ketamine, PER 24 and 36mg doses showed greater ARCI PCAG and Bad Drug Emax (p<0.001) but lower Drug Liking, Overall Drug Liking and Take Drug Again Emax (p<0.05); all PER doses also showed slower onset and longer duration of effect vs ketamine.Conclusions: Dose-related elevations were demonstrated in several measures of drug liking relative to placebo, indicating that supratherapeutic doses of PER may have some level of abuse potential. At therapeutic dose (8mg), PER showed statistically lower effects compared to alprazolam and ketamine on most measures. It is unlikely that therapeutic doses (4-12mg) of PER are associated with significant risk of drug abuse.