Pharmacokinetics and safety of adjunctive topiramate in infants (1-24 months) with refractory partial-onset seizures: a randomized, multicenter, open-label phase 1 study.

Purpose: To characterize the pharmacokinetics of adjunctive topiramate in infants (1-24 months) with refractory partial-onset seizures (POS); also to evaluate safety and tolerability of topiramate in the dose range of 3-25 mg/kg/day.

Methods: In this open-label phase 1 study, infants (N = 55) with refractory POS receiving at least one concurrent antiepileptic drug (AED) were enrolled. Infants were stratified by age and randomly assigned to one of four topiramate target dose groups (3-, 5-, 15-, or 25 mg/kg/day). Treatment was initiated at 3 mg/kg/day with titration to the target dose by weekly dose escalation. Topiramate was administered daily in two divided doses as oral liquid (5 mg/ml for infants <9 kg or those who could not tolerate solid foods) or sprinkle capsule (25 mg) formulations. Following seven consecutive days of topiramate administration at the target dose, four blood samples were collected from each infant for pharmacokinetic assessments (predose, 1-3, 4-6, and 8-10 h postdose).

Key Findings: Fifty-five infants (mean [SD] age in months: 11.4 [5.79]) with POS were enrolled, of whom 33% had seizures with or without secondary generalization. Complete pharmacokinetic profiles were obtained in 35 infants in whom mean plasma topiramate concentration-time profiles demonstrated linear pharmacokinetics (predose topiramate concentrations [C(trough) ] and area under the plasma concentration-time curve from time 0 through 12 h [AUC(12 h)]) of topiramate over the dose range studied). Apparent steady state oral clearance (CL(ss) /F) remained similar across all topiramate target dose groups and was independent of creatinine clearance, age, and weight. Mean values for CL(ss) /F were approximately twofold greater in infants receiving concomitant enzyme-inducing AEDs versus enzyme-inhibiting AEDs. Topiramate was well tolerated and safety findings were consistent with previous reports in children and adults. Most common treatment emergent adverse events (≥10%) were upper respiratory tract infection, fever, vomiting, somnolence, and anorexia.

Significance: In infants (1-24 months), topiramate exhibited linear steady state pharmacokinetics over the dose range 3-25 mg/kg/day, and CL(ss) /F of topiramate was independent of dose. Moreover, the concomitant enzyme-inducing AEDs doubled the clearance of topiramate. Topiramate was generally well tolerated as adjunctive therapy at doses up to 25 mg/kg/day.