Functional Half-Life is a Meaningful Descriptor of Steady-State Pharmacokinetics of an Extended-Release Formulation of a Rapidly Cleared Drug

Abstract and Introduction

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_½F) 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_½F was calculated to characterise divalproex-ER steady-state concentration-time profiles.
Methods: The value of t_½F, 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 (C_max) and minimum (C_min) plasma concentration and τ values, and calculated as ln(2)/(ln [C_max/C_min]/τ). The t_½F 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_½F 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_½F was 26.9 hours versus the expected elimination half-life of 6–12 hours.
Conclusion: The t_½F 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.

For many reasons, steady-state concentration-time profiles are often not optimally characterised by the intrinsic terminal elimination half-life for many drugs. Possible reasons include multi-exponential 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, the term 'effective´ half-life has often been used to characterise drug accumulation and time to steady-state pharmacokinetics.^{[1,2,3,4,5,6,7]} In the field of pharmacokinetics, the term 'functional´ half-life has been used to characterise the rate of decline in steady-state plasma concentrations over a dosing interval.^[8]

Valproic acid, commonly used in neuropsychiatry for treatment of epilepsy, bipolar disorder and prophylaxis of migraine headaches, has a short elimination half-life of 12–16 hours in adults taking the drug as monotherapy and an even shorter elimination half-life of 4–12 hours in other populations (e.g. children and hepatic enzyme-induced adult patients).^[9,10,11] Extended-release divalproex sodium (1:1 molar ratio of sodium valproate and valproic acid) tablets (Depakote^® ER, Abbott Laboratories, Abbott Park, IL, USA),¹ a once-daily formulation of valproic acid (hereafter referred to as divalproex-ER), is designed to release valproic acid over >18 hours.^[12] Hence, the steady-state valproic acid concentration-time profiles following divalproex-ER administration have small peak-trough fluctuations^[13] that are not adequately characterised by the valproic acid elimination half-life. In this report, we present a method for computing a practical and clinically relevant functional half-life (t_½F) that appropriately and optimally characterises the steady-state pharmacokinetics of a drug product with an extended (zero-order) and/or complex (mixed zero-/first-order) absorption-time profile. We use the divalproex-ER formulation of valproic acid to illustrate the utility of t_½F.

Clin Drug Invest. 2006;26(12):681-690. © 2006 Adis Data Information BV

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Cite this: Functional Half-Life is a Meaningful Descriptor of Steady-State Pharmacokinetics of an Extended-Release Formulation of a Rapidly Cleared Drug - Medscape - Dec 01, 2006.