Clinical Drug Investigation

, Volume 26, Issue 12, pp 681–690 | Cite as

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
  • Sandeep DuttaEmail author
  • Ronald C. Reed
Original Research Article


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.


Valproic Acid Dose Interval Breakthrough Seizure Valproic Acid Monotherapy Monoexponential Decline 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This study was sponsored by Abbott Laboratories, who also employ the authors.


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Copyright information

© Adis Data Information BV 2006

Authors and Affiliations

  1. 1.Abbott LaboratoriesAbbott ParkUSA

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