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

Abstract

SUMMARYPurpose: 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 . 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 enzymeinducing 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 enzymeinducing AEDs doubled the clearance of topiramate. Topiramate was generally well tolerated as adjunctive therapy at doses up to 25 mg/kg/day.

Advances in Pediatric Pharmacology, Therapeutics, and Toxicology

“…The oral liquid or sprinkle capsule formations were administered. In subjects with complete PK profiles (n=35), linear PK and dose proportionality were observed across all dose groups [71]. Drug clearance values on a per-kilogram basis were higher in infants (1-24 months) relative to published values in children and adolescents [71].…”

Pharmacotherapy for Seizures in Neonates with Hypoxic Ischemic Encephalopathy

“…Approximately 70% of the drug is eliminated unchanged in the urine. Data from children and adolescents aged 1-17 years of age indicate that infants exhibit higher clearance and shorter half-lives than older children [120,121]. Pharmacokinetic data for topiramate in babies with HIE is more limited.…”

Advances in Pediatric Pharmacology, Therapeutics, and Toxicology

“…A phase 1, safety and PK study sought to evaluate topiramate use in infants (n=55, 1–24 months of age) with refractory partial-onset seizures [71]. A total of four dose groups were evaluated: 3, 5, 15, or 25 mg/kg/day, with infants stratified into a dose group based on age category (1–6, 7–12, and 13–24 months).…”

“…In subjects with complete PK profiles (n=35), linear PK and dose proportionality were observed across all dose groups [71]. Drug clearance values on a per-kilogram basis were higher in infants (1–24 months) relative to published values in children and adolescents [71]. Patients receiving enzyme-inducing anti-epileptic drugs had two-fold higher clearance values.…”