No Effect of Gender or Age on Binding Characteristics of Valproic Acid to Serum Proteins in Pediatric Patients with Epilepsy

Abstract

The gender- and age-related binding characteristics of valproic acid to serum proteins were determined in the pediatric population. Serum samples examined in the study were obtained from 61 pediatric patients (28 males, 33 females) with epilepsy on valproic acid monotherapy. Their ages ranged from 1 to 15 years (mean age with [SD]: 7.8 [3.9] years; < 10 years, n = 41; > or = 10 years, n = 20). The in vivo population binding parameters of valproic acid to serum proteins and theoretical minimal unbound serum fraction (fu) of valproic acid were determined in (1) all, (2) male and female subgroups, and (3) prepubescent (< 10 years) and pubescent (> or = 10 years) subgroups. The association constant (K) was approximately 1.4 times higher in male (0.018 L/mumol) than in female (0.013 L/mumol) patients, while the total concentration of binding sites (n(Pt)) was 1.2 times greater in female (1235 mumol/L) than in male (997 mumol/L) patients. The fu was 0.053 and 0.059 for male and female patients, respectively. The value of K was approximately 1.6 times higher in the pubescent (0.019 L/mumol) than in the prepubescent (0.012 L/mumol) patients, while the n(Pt) was 1.2 times higher in the prepubescent (1244 mumol/L) than in the pubescent (1057 mumol/L) patients. The fu was 0.063 for the prepubescent and 0.047 for the pubescent patients. No significant differences were observed in binding characteristics of valproic acid to serum proteins between male and female or younger and older patients. However, the differences in valproic acid binding to serum proteins appear to be relatively larger in binding affinity than in binding capacity between the two groups. Because no significant differences were observed in serum concentrations of total and unbound valproic acid, albumin, or free fatty acids between any subgroups (male and female, younger and older), the results suggest that gender or age may not be factors for the determination of the binding characteristics of valproic acid to serum proteins in pediatric patients.

Characterization of non-linear relationship between total and unbound serum concentrations of valproic acid in epileptic children

“…The relationship between the total and unbound concentrations of VPA was altered in the case of patients treated with ethosuximide combination therapy or polytherapy (Table 2). The population means of B m (130·0 μg/mL, or 0·90 m m ) and K d (7·8 μg/mL, or 54 μ m ) calculated by taking account of this alteration are comparable with the reported values of 0·75–1·24 m m ( B m ) and 36–91 μ m ( K d ) (15, 16, 19, 22).…”

No effect of co-administered antiepileptic drugs on in-vivo protein binding parameters of valproic acid in patients with epilepsy

“…Free VPA fraction decreased significantly as serum albumin concentration increased in both groups (Figures 1a and 2a), and free VPA concentration increased non‐linearly depending on the total VPA concentration in both groups (Figures 1b and 2b). This is consistent with previous reports [25–27] . These results suggest that both serum albumin and total VPA concentration have to be considered to predict the protein‐binding characteristics of VPA.…”

Empirical Approach for Improved Estimation of Unbound Serum Concentrations of Valproic Acid in Epileptic Infants by Considering Their Physical Development

“…23,24) As shown in Table 4, the parameter Kd was determined not to be related to the physical development of the infants. Such a property of the parameter Kd was also observed in various studies previously reported, 10,25) and these results can be interpreted to reflect the fact that the serum albumin concentration in infants increases according to their physical development, while the protein-binding affinity of VPA is little affected by the physical development. 20,21) However, an additional investigation may be necessary to clearly explain that the protein-binding affinity in infants is not affected by the physical development, since it has been reported for various compounds that the protein-binding affinity to albumin decreases in infants, due to increased plasma concentrations of endogenous substances, including bilirubin and fatty acids.…”

“…In fact, there have been several studies on the estimation and/or a regression equation to predict the unbound from the total concentration. [9][10][11] However, as revealed in our previous study, the equation for epileptic children or adult patients is not applicable for epileptic infants aged less than 1 year old. The unbound serum VPA concentrations in infants vary patient by patient more markedly than those in children, and, thereby, their total and unbound VPA concentrations are poorly correlated (Fig.…”