Safety, tolerability, and pharmacokinetics of pregabalin in children with refractory partial seizures: a phase 1, randomized controlled study.
To evaluate the safety, tolerability, and pharmacokinetics (PK) of pregabalin as adjunctive therapy in children with refractory partial seizures.



This was a phase 1, randomized, placebo-controlled, parallel-group, escalating-dose, multiple-dose study comprising a 7-day, double-blind treatment period and a single-blind, single dose of pregabalin administered to all children on day 8. Children in four age cohorts (1-23 months, 2-6, 7-11, and 12-16 years) received one of four doses of pregabalin (2.5, 5, 10, or 15 mg/kg/day) or placebo. Safety and tolerability were assessed throughout the study. Steady-state and single-dose PK parameters on day 8 were analyzed using standard noncompartmental procedures.



Sixty-five children received at least one dose of treatment. Four pregabalin-treated children discontinued treatment, three of whom received 15 mg/kg/day. Two children experienced serious adverse events, one of whom received pregabalin 15 mg/kg/day. During double-blind treatment, the most common adverse events reported in the pregabalin-treated population were somnolence (27.1%) and dizziness (12.5%). Steady-state pregabalin peak and total exposure in each age cohort appeared to increase linearly with dose. Apparent oral clearance (CL/F) was directly related to creatinine clearance, consistent with adults. CL/F normalized for body weight was 43% higher in patients weighing <30 kg. Steady-state and single-dose PK were consistent.



Pregabalin at doses up to 10 mg/kg/day in children aged 1 month to 16 years, and at doses up to 15 mg/kg/day in those aged <6 years, demonstrated acceptable safety and tolerability. For children weighing <30 kg, a dose increase of 40% (mg/kg dosing) is required to achieve comparable exposure with adults or children weighing ≥30 kg. These data will inform dose selection in phase 3 trials of the efficacy and safety of adjunctive pregabalin in children with refractory partial seizures.
Pfizer Inc, Groton, Connecticut, U.S.A.
Donald
D
Mann
Jing
J
Liu
Marci L
ML
Chew
Howard
H
Bockbrader
Christine W
CW
Alvey
Elizabeth
E
Zegarac
John
J
Pellock
Verne W
VW
Pitman
D000293:Adolescent; D000927:Anticonvulsants / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D019540:Area Under Curve; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004562:Electrocardiography; D004828:Epilepsies, Partial / Q000097:blood* / Q000188:drug therapy* / Q000652:urine; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D000069583:Pregabalin; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use
D000927:Anticonvulsants; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid
Epilepsy; Pediatric; Pharmacokinetics; Pregabalin; Safety; Tolerability