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 (t½F) has often been used to characterise steady-state pharmacokinetics. Valproic acid, commonly used in neuropsychiatry, has an elimination half-life of 416 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 t½F was calculated to characterise divalproex-ER steady-state concentration-time profiles.
Methods: The value of t½F, 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 t½F 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 614 days.
Results: The estimated geometric mean t½F in uninduced adults was 40.0 hours versus the expected elimination half-life of 1216 hours in this population (including patients on valproic acid monotherapy); for induced patients, t½F was 26.9 hours versus the expected elimination half-life of 612 hours.
Conclusion: The t½F 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.
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.
Valproic acid, commonly used in neuropsychiatry for treatment of epilepsy, bipolar disorder and prophylaxis of migraine headaches, has a short elimination half-life of 1216 hours in adults taking the drug as monotherapy and an even shorter elimination half-life of 412 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. Hence, the steady-state valproic acid concentration-time profiles following divalproex-ER administration have small peak-trough fluctuations 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 (t½F) 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 t½F.
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.