Apparent clearance of valproic acid in elderly epileptic patients: estimation of the confounding effect of albumin concentration

Natalia Lampon,J Carlos Tutor

doi:10.3109/03009734.2011.640412

Abstract

Background. Valproic acid (VPA) apparent clearance (CL) estimated from total serum concentrations is analogous in elderly and non-elderly adult patients. As drug–protein binding decreases in old age, the aim of our study was to evaluate the confounding effect of the serum albumin concentration on the VPA apparent CL in elderly patients.Methods. In 102 epileptic out-patients treated with VPA in monotherapy, serum total steady-state trough concentrations (Css) were determined. Css concentrations were normalized for a 42 g/L albumin concentration (CssN), and the apparent CL and normalized apparent CLN were calculated.Results. A poor concordance of 53% was found in the classification of Css and CssN levels of VPA as subtherapeutic, therapeutic, or supratherapeutic dose. In the elderly (≥65 years) and non-elderly adult patients, the VPA apparent CL was similar; however, normalized apparent CLN was significantly lower in older patients (P < 0.01), with a 40% median decrease.Conclusions. Total VPA concentrations should be interpreted with caution, mainly in older patients, in which determination of unbound or normalized total drug concentrations may be clinically useful. Normalization of total concentrations permits an estimation of the masking effect of serum albumin concentrations on the VPA apparent CL in elderly patients.

Highlights

Valproic acid (VPA) was initially approved for the treatment of refractory absence seizures, it is recognized that it has a broad-spectrum antiepileptic activity [1]
There was a negative correlation between the serum albumin concentration and age (r = –0.462, P < 0.001), with patients older than 65 years of age presenting a significant decrease of the albumin concentration (P < 0.001) (Table I)
In accordance with previously published reports [7,8,9,10], the apparent CL of VPA calculated from the total Css concentrations was analogous in elderly and non-elderly adult patients (Table I); the serum concentration of albumin was significantly lower in the group with age ‡65 years than in the other groups that were considered (Table I), and an increase of the VPA unbound fraction should be assumed in these elderly patients, as previously described [5,11,21,22]

Summary

Introduction

Valproic acid (VPA) was initially approved for the treatment of refractory absence seizures, it is recognized that it has a broad-spectrum antiepileptic activity [1]. The apparent clearance (CL) calculated from total serum VPA concentrations is similar in elderly and non-elderly adult patients [7,8,9,10]; in a clinical context these findings must be interpreted with caution, considering that VPA plasma protein binding decreases in old age, with an accompanying increase of the free fraction of the drug [5,8,11]. Valproic acid (VPA) apparent clearance (CL) estimated from total serum concentrations is analogous in elderly and non-elderly adult patients. As drug–protein binding decreases in old age, the aim of our study was to evaluate the confounding effect of the serum albumin concentration on the VPA apparent CL in elderly patients. Normalization of total concentrations permits an estimation of the masking effect of serum albumin concentrations on the VPA apparent CL in elderly patients

Objectives

Methods

Results

Conclusion