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.
Methods: The value of t1/2F, defined as the time taken for the concentration to drop by one-half during a dosing interval (τ) at steady state, was derived using steady-state maximum (Cmax) and minimum (Cmin) plasma concentration and τ values, and calculated as ln(2)/(ln [Cmax/Cmin]/τ). The t1/2F 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 t1/2F 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, t1/2F was 26.9 hours versus the expected elimination half-life of 6–12 hours.
Conclusion: The t1/2F of valproic acid optimally characterises the expected steady-state Cmax to Cmin decrease of 33% in uninduced and 45% in induced adults following once-daily administration of divalproex-ER.
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This study was sponsored by Abbott Laboratories, who also employ the authors.
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