Papers of the Week

Ampakines, AMPA-type glutamate receptors (AMPAR) positive allosteric modulators, possess the capacity to treat neurological and neuropsychiatric disorders underpinned by deficient excitatory synaptic communication. Low-impact ampakines partially offset AMPAR desensitization which may explain their lack of epileptogenic effects and acceptable safety margins in preclinical studies. The low-impact ampakine CX717 has shown efficacy in prior preclinical studies and the ability to prevent opiate-induced respiratory depression in humans. The current clinical study examines the tolerability and pharmacokinetics of CX717 in healthy male subjects and elderly male and female subjects in a four-part study. Part A was a single dose escalation study (25-1600 mg, 72 subjects). Part B was a two-period food effect crossover study (100 mg, 8 subjects). Part C was a multiple dose escalation study (100 mg QD – 800 mg BID, 10 days, 32 subjects), and Part D was a multiple dose study of CX717 (300 mg QD, 10 days, 7 males and 8 females) in elderly subjects. CX717 was well tolerated up to 1600 mg and 800 mg BID. CX717 was also well tolerated when fed or fasted and was well tolerated in the elderly with prominent side effects being headache, dizziness and nausea. The half-life of CX717 was 8-12 h, and T was 3-5 h. C and AUC were dose-proportional. These findings provide key dosing and safety pharmacology data that can be used to inform further investigations of CX717 in subsequent clinical studies such as ADHD, opiate-induced respiratory depression and spinal cord injury.