Functional Half-Life is a Meaningful Descriptor of Steady-State Pharmacokinetics of an Extended-Release Formulation of a Rapidly Cleared DrugAs Shown by Once-Daily Divalproex-ER

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 (t1/2F) 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 t1/2F was calculated to characterise divalproex-ER steady-state concentration-time profiles.