Population estimation of valproic acid clearance in adult patients using routine clinical pharmacokinetic data

Abstract

The aim of the present study was to estimate valproic acid (VPA) clearance values for adult patients with epilepsy, using serum concentrations gathered during their routine clinical care. Retrospective steady state serum concentrations data (n=534) collected from 208 adult patients receiving VPA were studied. Data were analysed according to a one‐compartment model using the NONMEM program. The influence of VPA daily dose (Dose), gender, age, total body weight (TBW), and comedication with carbamazepine (CBZ), phenytoin (PHT) and phenobarbital (PB) were investigated. The results of the population pharmacokinetics analysis were validated in a group of 30 epileptic patients. The final regression model for VPA clearance (Cl) was: The inter‐individual variability in VPA clearance, described by a proportional error model, had a variation coefficient (CV) of 23.4% and the residual variability, described using an additive model, was 11.4 mg/L. These results show that VPA clearance increased linearly with TBW, but increases nonlinearly with increasing VPA daily dose. Concomitant administration of CBZ, PHT and PB led to a significant increase in VPA clearance. The model predictions in the validation group were found to have satisfactory precision and bias. In conclusion, inter‐individual variability in VPA clearance can be partly explained by TBW, daily dose and bitherapy with CBZ, DPH or PB. Inclusion of these factors allows this variability to be reduced by 37.23% which may be very useful for clinicians when establishing the initial VPA dosage regimen. However, the magnitude of inter‐individual plus residual variabilities, remaining in the final model, render these dosage predictions imprecise and justify the need for VPA serum level monitoring in order to individualize dosage regimens more accurately. Copyright © 1999 John Wiley & Sons, Ltd.

Population Pharmacokinetics of Valproic Acid in Adult Chinese Epileptic Patients and its Application in an Individualized Dosage Regimen

“…which satisfy the above 2 features. [6][7][8]11,12 This relationship is consistent with the concept of the concentration-dependent binding of VPA to proteins. Patient demographic and medication details were also carefully recorded, which imparted greater accuracy and reliability to the data used in the VPA model.…”

Influence of Concomitant Antiepileptic Drugs on Plasma Lamotrigine Concentration in Adult Japanese Epilepsy Patients

“…According to a study on the pharmacokinetics of VPA, its clearance was increased about 1.5-fold by concomitant administration of PHT in comparison with VPA monotherapy, which was higher than seen with concomitant administration of PB or CBZ. 28) Thus, LTG metabolism is induced in the same manner as VPA. May et al 10) reported no statistically significant difference between the CD ratio for LTG and the PHT concentration.…”

Valproic acid pathway

“…The dose requirements for VPA are highly variable (10-fold differences in mean dose in adults) [4] and interactions with other drugs are common (discussed below). Therapeutic drug monitoring is commonly used, although both the clinical and toxic effects of the drug are considered to be poorly correlated with total serum concentrations [3].…”