Variability in Level‐Dose Ratio of Valproate: Monotherapy Versus Polytherapy

Abstract

One of the most useful pharmacokinetic parameters of a drug is the level‐dose ratio. This ratio originates from a relationship between the dosing rate (i.e., the daily dose) and the corresponding steady‐state plasma level. For most drugs that relationship is linear, indicating that changes in doses are associated with proportional changes in plasma levels. This proportionality between plasma level and dose is an expression of the fact that the clearance of the drug is constant. Valproic acid has been available in a number of countries for over a decade, and in spite of the large number of pharmacokinetic studies available in the literature, it is not possible, at the present time, to define a characteristic level‐dose ratio. This situation is a result of the fact that the clearance of valproate exhibits large interpatient variability. This article presents an analysis of the causes for the variability in valproate clearance. It is shown that when the determinants of valproate clearance are understood and taken into consideration, only a few factors are found to have a profound influence on it. Most important among these are age and polytherapy.