Safety, tolerability, and pharmacokinetics of pregabalin in children with refractory partial seizures: a phase 1, randomized controlled study

Epilepsia. 2014 Dec;55(12):1934-43. doi: 10.1111/epi.12830. Epub 2014 Nov 6.


Objective: To evaluate the safety, tolerability, and pharmacokinetics (PK) of pregabalin as adjunctive therapy in children with refractory partial seizures.

Methods: 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.

Results: 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.

Significance: 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.

Trial registration: NCT00437281.

Keywords: Epilepsy; Pediatric; Pharmacokinetics; Pregabalin; Safety; Tolerability.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Anticonvulsants / pharmacokinetics*
  • Anticonvulsants / therapeutic use*
  • Area Under Curve
  • Child
  • Child, Preschool
  • Cohort Studies
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Drug Administration Schedule
  • Electrocardiography
  • Epilepsies, Partial / blood*
  • Epilepsies, Partial / drug therapy*
  • Epilepsies, Partial / urine
  • Female
  • Humans
  • Infant
  • Male
  • Pregabalin
  • Time Factors
  • Tomography, X-Ray Computed
  • Treatment Outcome
  • gamma-Aminobutyric Acid / analogs & derivatives*
  • gamma-Aminobutyric Acid / pharmacokinetics
  • gamma-Aminobutyric Acid / therapeutic use


  • Anticonvulsants
  • Pregabalin
  • gamma-Aminobutyric Acid

Associated data