Pharmacokinetic parameters of valproic acid monotherapy in pediatric patients with epilepsy : estimation from total and unbround serum concentrations

Abstract

This study evaluate the pharmacokinetic parameters of total and unbound valproic acid (VPA) in pediatric with epilepsy. Measured total and unbound steady state serum concentrations of VPA at trough and at 5th hours after morning dose in pediatric patients who were receiving valproic acid as monotherapy. The free fractions and the pharmacokinetic parameters of total and unbound VPA were calculated, compared by t-test and defined the correlation with patient’s characteristics by stepwise. There were twenty-nine children enrolled in the study. High relationship between total and unbound concentrations was found, the equation for predicting unbound concentration from total concentration was unbound concentration = -6.01 + 0.18*total concentration (r2 = 0.78). The mean fraction of unbound VPA ranged from 7.1% at low total levels (≤50µg/mL), 9.8% at medium levels (50-100 µg/mL) up to 13.5% at high levels (>100µg/mL). There were substantial differences in the pharmacokinetic parameters of unbound and total VPA. Elimination rate constant (Ke) and clearance of total drug (0.068 ± 0.03 hr-1 and 12.37 ± 4.16 mL/kg/hr) were significantly less than those of unbound VPA (0.103 ± 0.08 hr-1 and 101.03 ± 33.39 mL/kg/hr). The apparent volume of distribution (Vd) of total VPA was 0.183 ± 0.08 L/kg while that of the unbound VPA was 1.316 ± 0.84 L/kg indicated considerable distribution of unbound VPA to extravascular. The terminal half-life of unbound VPA (9.20 ± 5.34 hr) was significantly shorter (P < 0.05) than that of the total VPA (11.50 ± 4.05 hr). There were correlation between pharmacokinetic parameters and demographic data. Some pharmacokinetic parameters of total VPA could be well predicted from the demographic data, for example, Cl = 4.813 + 0.247 daily dose (r2 = 0.693) and Ɩn CI = 2.316 + 0.0157 daily dose - 0.0145 weight (r2 = 0.739), Ɩn t1/2 = 1.037 + 0.656age (r2 = 0.525). However, no good prediction of the pharmacokinetic parameters for unbound VPA could be obtained from the demographic data. The results provided a more rational understanding of VPA pharmacokinetics in the clinical setting and may be useful for the monitoring and manipulation of VPA therapy in epileptic children.