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Pharmacokinetics of total and free valproic acid during monotherapy in infants
L Herngren1, B Lundberg, A Nergårdh
1Department of Clinical Pharmacology, Karolinska Hospital, Stockholm, Sweden.
Insights
This study investigated valproic acid (VPA) pharmacokinetics in infants. VPA clearance was higher and protein binding lower in infants compared to adults, with unbound VPA increasing at higher concentrations.
Area of Science:
- Pharmacology
- Pediatric Medicine
- Clinical Pharmacy
Background:
- Valproic acid (VPA) is a widely used antiepileptic drug.
- Infant pharmacokinetics often differ significantly from adults due to developmental changes.
- Understanding VPA disposition in infants is crucial for safe and effective dosing.
Purpose of the Study:
- To characterize the pharmacokinetics of free and total valproic acid in plasma and whole blood of infants.
- To compare VPA pharmacokinetic parameters between infants and older populations.
- To investigate factors influencing VPA protein binding and clearance in infants.
Main Methods:
- Oral administration of VPA monotherapy to seven infants (mean age 10.7 months).
- Measurement of free and total VPA concentrations in plasma and whole blood at steady state.
- Analysis of pharmacokinetic parameters including half-life, clearance, and protein binding.
Main Results:
- Whole blood VPA concentrations mirrored plasma levels but were lower.
- VPA half-lives were longer for total VPA than free VPA and decreased with age.
- Infant VPA clearance was significantly higher than in adults, correlating with lower protein binding (mean 85.3%).
- Unbound VPA fraction increased with total VPA concentration and was higher in infants with low albumin.
Conclusions:
- Infants exhibit distinct VPA pharmacokinetic profiles compared to adults, characterized by higher clearance and lower protein binding.
- Age and albumin concentration are important factors influencing VPA unbound fraction and disposition in infants.
- These findings highlight the need for careful VPA dose individualization in pediatric populations.
Abstract:
The pharmacokinetics of free and total valproic acid (VPA) in plasma and whole blood after oral administration during steady state was investigated in seven infants (mean age 10.7 months) receiving monotherapy. The VPA concentrations in whole blood closely followed those in plasma but at a reduced level. A positive correlation was found between dose and mean plasma concentration (r = 0.71). Mean terminal half-lives were similar in plasma and whole blood (12.5 and 15.5 h, respectively), but were considerably longer than for free VPA (6.4 and 6.5 h, respectively; P less than 0.01). There was a significant decrease in half-lives with increasing age (P less than 0.05). Plasma and whole blood clearance for total VPA was higher than reported in older infants and adults (17.8 and 28.9 ml/kg per hour) and was considerably higher for free VPA (127.6 and 188.8 ml/kg per hour, respectively). The increase in clearance compared with that in older subjects is well in concordance with a lower protein binding of VPA (mean 85.3%). Of special importance is that the percentage of unbound VPA increased with increasing concentrations of total VPA. The fraction of unbound VPA in plasma increased even more in subjects with low albumin concentrations (P less than 0.01).