Comparison of Two Binding Equations for Prediction of the Concentration of Unbound Valproic Acid in the Serum of Adult Epileptic Polytherapy Patients

Abstract

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.

Clinical Importance of Monitoring Unbound Valproic Acid Concentration in Patients with Hypoalbuminemia

“…Because laboratory measurement of unbound VPA concentration is not readily available, we proposed an equation for the correction of total VPA concentration according to albumin concentration (Table ). This equation is more convenient and easy to use compared with previously published derived formulas . However, our equation should be used with caution because it has been neither validated in a large population nor been retested by another group of clinicians.…”

“…This equation is more convenient and easy to use compared with previously published derived formulas. 6,18,24,25 However, our equation should be used with caution because it has been neither validated in a large population nor been retested by another group of clinicians. Also, other factors that may affect the binding of VPA to albumin (e.g., uremia or renal failure, chronic liver disease, hyperbilirubinemia, hypertriglyceridemia, and drug interactions) were not taken into consideration by the equation.…”

“…However, to our knowledge, no equation for predicting unbound VPA concentration is available in clinical practice. Indirect methods for estimating the free fraction of VPA were proposed, as well as a total VPA concentration correction model for albumin based on the estimation of the free fraction (free fraction [%] = 130.69∙e (−0.00496∙serum albumin concentration) , where albumin is expressed in μmol/L) . These methods have not been validated and are not practical, unlike equations developed for phenytoin .…”

“…Indirect methods for estimating the free fraction of VPA were proposed, as well as a total VPA concentration correction model for albumin based on the estimation of the free fraction (free fraction [%] = 130.69•e (À0.00496•serum albumin concentration) , where albumin is expressed in lmol/ L). 6,18,24,25 These methods have not been validated and are not practical, unlike equations developed for phenytoin. 23 Therefore, these models have not replaced the determination of unbound VPA concentration in clinical practice.…”

Derivation and Validation of a New Equation for Estimating Free Valproate Concentration in Critically Ill Adult Patients

“…Total VPAC are discordant with measured free VPAC in 70-87% of ICU patients (9,10). The limited availability of free VPAC assays has spurred the development of care equation-based models to predict free VPAC (13)(14)(15)(16)(17). However, none of them included ICU patients (13)(14)(15)(16)(17).…”