Abstracts

Rationale: Pregabalin (PGB) is indicated for epilepsy as adjunctive therapy for adults with partial onset seizures (POS). The study objective was to evaluate single- and multiple-dose safety and tolerability of PGB and single-dose and steady-state pharmacokinetics (PK) of PGB in epilepsy patients 1 month to 16 years with POS.Methods: This was a parallel-group, multiple-dose, dose escalation study in children 1 month through 16 years, with POS and receiving adjunctive treatment (1-3 AEDs). Sixty-five subjects were enrolled and stratified among 4 age cohorts (1 - 23 months, 2 - 6 years, 7 - 11 years, 12 - 16 years) with 4 incremental dose escalation levels (2.5, 5, 10, and 15 mg/kg/day). For each age/dose level, subjects were to be randomized in a 3:1 ratio between PGB and placebo. PGB or placebo was administered orally every 12 hours for 7 days. On Day 8, all subjects received a single morning dose of PGB. Serial PK blood samples were collected and PK parameters determined using standard non-compartmental methods. Tolerability and safety assessments were performed pre- and post-dosing.Results: Peak PGB plasma concentrations were generally observed between 0.5 to 2 hours post-dose when PGB was administered in the fasted state, similar to the T_max in adults. PGB peak (C_max) and total (AUC) exposure appeared to increase linearly with daily dose within each age group. Across age groups, PGB AUC was approximately 30% lower in pediatric subjects < 30 kg of body weight than in those weighing > 30 kg. Accordingly, PGB clearance normalized per body weight (mL/min/kg) was approximately 43% higher in the children with body weight < 30 kg versus those > 30 kg. Oral clearance of PGB (mL/min) was directly related to creatinine clearance. PGB half-life (t ) averaged about 3 to 4 hours in pediatric subjects from 1 month to 6 years, and 4 to 6 hours in those 7 years and older. The adverse event (AE) profile observed in subjects 1 month to 16 years was similar to that observed in adults, with somnolence and dizziness being the most commonly reported. PGB doses up to and including 10 mg/kg/day were well tolerated in all age groups. The 15 mg/kg/day dose was not sufficiently well tolerated in the age cohorts with subjects 7 years of age and older (higher rate of drug discontinuations and serious AEs). In subjects 1 month to 6 years, the 15 mg/kg dose level yielded exposures similar to 10 mg/kg/day in the older age cohorts, and was sufficiently well tolerated.Conclusions: Following oral administration in children, PGB C_max and AUC generally appeared to increase linearly with dose within each age group and PGB AUC was approximately 30% lower in subjects < 30 kg when PGB was administered on a mg/kg basis. PGB was safe and well tolerated in pediatric epilepsy patients with POS following doses providing exposures comparable to 10 mg/kg/day.