Empirical approach for improved estimation of unbound serum concentrations of valproic acid in epileptic infants by considering their physical development

The unbound serum concentration of valproic acid (VPA) is closely related to its therapeutic efficacy. In epileptic infants, the unbound VPA concentration varies largely from patient to patient, being difficult to predict using the reported equations for older children. To establish an equation to estimate the unbound concentration in infants, we empirically characterized the relationship between total and unbound VPA concentrations, taking their growth and development into consideration. Data were retrospectively collected from archived clinical records of 30 epileptic infants aged 0-11 months old. The relationship between total and unbound VPA concentrations was analyzed according to the Langmuir equation, in which the patient's body weight, height, and body surface area were considered as physical development indices. Inter- and intra-individual variabilities in the VPA concentrations were also considered. It was shown that the unbound VPA concentration in infants is properly estimated when their body weights are taken into account, in which the parameter for the maximum binding site concentration (Bm) increases as the body weight increases, while that for the dissociation constant (Kd) is unaltered. Additionally, the relationship was shown to slightly change when the infants are concomitantly treated with VPA and the other antiepileptics. These findings provide useful information to adjust the VPA dosage to achieve optimal therapeutic efficacy in epileptic infants.