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A single-dose study to define tiagabine pharmacokinetics in pediatric patients with complex partial seizures
L E Gustavson1, S W Boellner, G R Granneman
1Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, IL 60064-3500, USA.
Insights
This study on tiagabine in children with complex partial seizures found that valproate significantly increased drug exposure and prolonged its half-life. Tiagabine was well tolerated in pediatric patients.
Area of Science:
- Pharmacology
- Pediatric Neurology
- Clinical Pharmacology
Background:
- Complex partial seizures are a common form of epilepsy in children.
- Antiepilepsy drugs (AEDs) can have altered pharmacokinetics in pediatric populations.
- Understanding drug interactions is crucial for effective epilepsy management in children.
Purpose of the Study:
- To assess the pharmacokinetics and safety of tiagabine in children with complex partial seizures.
- To evaluate the impact of concomitant antiepilepsy drugs (AEDs) on tiagabine pharmacokinetics.
- To compare tiagabine pharmacokinetics in children receiving valproate versus enzyme-inducing AEDs.
Main Methods:
- An open-label study involving 25 children with complex partial seizures.
- Administration of a single dose of tiagabine (approximately 0.1 mg/kg).
- Concomitant use of individual AED regimens, including enzyme-inducing AEDs (carbamazepine, phenytoin) or valproate.
Main Results:
- Tiagabine was well tolerated in all pediatric participants.
- Children taking valproate showed significantly higher dose-normalized area under the plasma concentration-time curve (AUC) and longer half-life compared to those on inducing AEDs.
- Oral clearance of tiagabine was approximately half in children taking valproate versus induced children.
- Body size explained 40-50% of the variability in tiagabine clearance and volume of distribution.
Conclusions:
- Valproate significantly increases tiagabine exposure and prolongs its elimination in children.
- Tiagabine pharmacokinetics in children show similarities to adult patterns when considering concomitant AEDs.
- Pediatric patients may exhibit higher tiagabine clearance and volume of distribution per body weight compared to adults.
Abstract:
We report an open-label study of 25 children with complex partial seizures that assessed the pharmacokinetics and safety of a single dose of approximately 0.1 mg/kg tiagabine. The children received their usual individualized regimen of one concomitant antiepilepsy drug (AED) throughout the study. Seventeen children were receiving an inducing AED (carbamazepine or phenytoin); eight were receiving valproate. Tiagabine was well tolerated. Dose-normalized Cmax was higher in children taking valproate (18.2 +/- 5.0 ng/mL/mg) than in the induced children (14.8 +/- 6.9 ng/mL/mg), but the difference was not statistically significant. Dose-normalized area under the plasma concentration-time curve from time zero to infinite time was significantly higher (p = 0.002) in children taking valproate (176.5 +/- 54.7 ng.hr/mL/mg) than in induced children (92.4 +/- 56.7 ng.hr/mL/mg). Similarly, oral clearance in the children taking valproate (96 +/- 39 mL/min) was half that of the induced children (207 +/- 91 mL/min). Half-life in children taking valproate (5.7 hr) was almost twice that for the induced children (3.2 hr), and the elimination rate constant was significantly lower (p < 0.02) for the children taking valproate than for the induced children. Volume of distribution was similar in the children taking valproate (52 +/- 9 L) and the induced children (59 +/- 29 L). This is consistent with observations in adults taking tiagabine with inducing AEDs or valproate. Exploratory regressions on these data in children and previous data in adults showed fairly strong relationships between body size and tiagabine clearance and volume of distribution, with body size explaining about 40 to 50% of the variability. When adjusted per kg body weight, clearance and volume were greater in children than adults. When adjusted per m2 body surface area, clearance and volume were more similar in adults and children.