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.

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This study evaluated the utility of combination of digoxin (0.25 mg) and rosuvastatin (5 mg) as a new transporter (P‐glycoprotein/breast cancer resistance protein/organic anion‐transporting polypeptide (OATP)1B1/OATP1B3) probe cocktail (Oita combination) for drug–drug interaction (DDI) studies by demonstrating lack of DDI of digoxin on the pharmacokinetics (PKs) of rosuvastatin, as it was already known that rosuvastatin did not affect digoxin PK. This was an open‐label, two‐period study in which the primary end points were the geometric mean ratio (GMR) of the area under the plasma rosuvastatin concentration‐time curve from time zero to last (AUC last) after rosuvastatin administration combined with digoxin to that after rosuvastatin administration alone and its 90% confidence interval (CI). As the GMR of AUC last was 0.974 and its 90% CI was 0.911–1.042, it was judged that digoxin does not affect rosuvastatin PK. Results of this study have rationalized utility of the Oita combination as a transporter probe cocktail for clinical DDI studies.

Because binding of valproic acid to plasma proteins affects the efficacy of the drug in the treatment of epilepsy (only the unbound fraction of the drug is effective) we have compared two methods which use different binding parameters to predict the in-vivo concentration of unbound valproic acid in serum. The study was performed on 46 serum samples from 29 polytherapy adult patients with epilepsy. Mean prediction error, mean absolute prediction error and root mean squared error were calculated for each method; these values served as a measure of prediction bias and precision. The mean absolute prediction errors and root mean squared errors for the two methods were similar in magnitude (Method 1, mean absolute prediction error = 10.0 microM, root mean squared error = 15.0 microM; Method 2, mean absolute prediction error = 10.3 microM, root mean squared error = 13.5 microM). Method 2 had a general tendency to over-predict unbound valproic acid; both methods had a tendency to over-prediction for total concentrations above 500 microM. Method 1 had a tendency to under-prediction at total concentrations below 250 microM. Within the total concentration range of valproic acid investigated, Method 1 was superior to Method 2 for prediction of unbound serum valproic acid. Our approach using Method 1 may be useful for prediction of unbound serum valproic acid concentration in patients with total valproic acid concentrations ranging from 250 to 500 microM; Method 2 may be useful for patients with total valproic acid below 500 microM. Our results suggest that there is wide and unpredictable variability in valproic acid binding to serum proteins among study populations.