Topiramate pharmacokinetics in infants
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Published on: June 25, 2016
T A Glauser1, M V Miles, P Tang
1Children's Comprehensive Epilepsy Program, Department of Neurology, Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039, USA.
Insights
Infants may need higher topiramate (TPM) doses than older individuals. Weight-based dosing and titration to effect are crucial for managing infantile spasms with TPM.
Area of Science:
- Pharmacology
- Pediatric Neurology
- Clinical Pharmacy
Background:
- Infantile spasms (IS) are a severe epilepsy syndrome in infants.
- Topiramate (TPM) is used for refractory IS, but its pharmacokinetics in infants are not well-established.
Purpose of the Study:
- To determine the pharmacokinetics of topiramate (TPM) in infants younger than 4 years with refractory infantile spasms.
- To provide preliminary data for optimizing TPM dosing in this population.
Main Methods:
- Assessed TPM pharmacokinetics in 5 infants receiving stable doses for over 7 days.
- Collected blood samples at multiple time points post-dose for TPM concentration analysis.
- Utilized noncompartmental analysis to calculate pharmacokinetic profiles.
Main Results:
- TPM pharmacokinetics in infants appeared linear.
- Mean TPM plasma clearance (CL/F) was higher in infants compared to children, adolescents, and adults.
- Concomitant enzyme-inducing antiepileptic drugs (AEDs) increased TPM CL/F and shortened its half-life.
Conclusions:
- Infants may require higher weight-based topiramate doses than older age groups.
- Therapeutic decisions for TPM in infants should prioritize titration to effect over absolute dose.
Purpose:
This study's goal was to provide preliminary data on the pharmacokinetics of topiramate (TPM) in a cohort of infants (younger than 4 years) participating in an open-label trial of TPM in refractory infantile spasms.
Methods:
The pharmacokinetics of TPM were assessed in infants receiving a stable TPM dose for >7 days during the extension phase of this trial. Blood samples were drawn just before and 0.5. 1, 1.5, 2, 4, 6, 8, and 12 h after the morning TPM dose. TPM plasma concentrations were determined by fluorescence polarization immunoassay. The noncompartmental analysis module of WinNonlin was used to calculate individual patient pharmacokinetics profiles.
Results:
Five infants (ages, 23.5-29.5 months) formed the study cohort. These infants had been given TPM for a median of 9 months (range, 6-11 months) and were currently receiving between 11 and 38.5 mg/kg/day TPM. One was receiving TPM monotherapy, whereas four were taking concomitant antiepileptic medications (AEDs; n = 2, enzyme-inducing agents; n = 2, non-enzyme-inducing drugs). TPM pharmacokinetics in infants appears to be linear. In this cohort, mean TPM plasma clearance (CL/F, 66.6+/-27.4 ml/h/kg) was slightly higher than that reported for children and adolescents and therefore substantially higher than that reported for adults. TPM CL/F was higher and the calculated half-life shorter in the infants receiving concomitant enzyme-inducing AEDs.
Conclusions:
Based on this small cohort of patients, it appears that infants may require significantly larger TPM doses, based on weight, than children, adolescents, or adults. Titration to effect and not absolute TPM dose should guide therapy in this age group.
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