Functional half-life is a meaningful descriptor of steady-state pharmacokinetics of an extended-release formulation of a rapidly cleared drug : as shown by once-daily divalproex-ER

Abstract

Background: For many drugs, steady-state concentration-time profiles are often not optimally characterised by the intrinsic terminal elimination half-life for various reasons, including multiexponential disposition with minimal contribution of the terminal phase to steady-state exposure or use of controlled-release formulations with extended zero- or mixed zero-/first-order absorption. In such cases, 'effective' or 'functional' half-life (t((1/2)F)) has often been used to characterise steady-state pharmacokinetics. Valproic acid, commonly used in neuropsychiatry, has an elimination half-life of 4-16 hours in different populations (children vs adults, enzyme-induced vs uninduced). Divalproex-ER, a once-daily extended- release divalproex sodium formulation, is designed to release valproic acid over >18 hours. Hence the steady-state divalproex-ER concentration-time profiles have small peak-trough fluctuations that are not optimally characterised by valproic acid elimination half-life. In this study, the value of t((1/2)F) was calculated to characterise divalproex-ER steady-state concentration-time profiles.

Methods: The value of t((1/2)F), defined as the time taken for the concentration to drop by one-half during a dosing interval (tau) at steady state, was derived using steady-state maximum (C(max)) and minimum (C(min)) plasma concentration and tau values, and calculated as ln(2)/(ln [C(max)/C(min)]/tau). The t((1/2)F) values of valproic acid in adult hepatic enzyme-uninduced healthy subjects and enzyme-induced epilepsy patients were calculated from five pharmacokinetic studies in which divalproex-ER was administered once daily for 6-14 days.

Results: The estimated geometric mean t((1/2)F) in uninduced adults was 40.0 hours versus the expected elimination half-life of 12-16 hours in this population (including patients on valproic acid monotherapy); for induced patients, t((1/2)F) was 26.9 hours versus the expected elimination half-life of 6-12 hours.

Conclusion: The t((1/2)F) of valproic acid optimally characterises the expected steady-state C(max) to C(min )decrease of 33% in uninduced and 45% in induced adults following once-daily administration of divalproex-ER.