The Operational Multiple Dosing Half-life: A Key to Defining Drug Accumulation in Patients and to Designing Extended Release Dosage Forms

Abstract

Half-life (t _1/2) is the oldest but least well understood pharmacokinetic parameter, because most definitions are related to hypothetical 1-compartment body models that don’t describe most drugs in humans. Alternatively, terminal half-life (t _1/2,z) is utilized as the single defining t _1/2 for most drugs. However, accumulation at steady state may be markedly over predicted utilizing t _{1/2, z}. An apparent multiple dosing half-life (t _{1/2, app}) was determined from peak and trough steady-state ratios and found to be significantly less than reported terminal t _1/2s for eight orally dosed drugs with t _1/2,z values longer than one day. We define a new parameter, “operational multiple dosing half-life” (t _{1/2, op}), as equal to the dosing interval at steady-state where the maximum concentration at steady-state is twice the maximum concentration found for the first dose. We demonstrate for diazepam that the well-accepted concept that t _1/2,z representing the great majority of the AUC will govern accumulation can be incorrect. Using oral diazepam, we demonstrate that t _{1/2, op} is remarkably sensitive to the absorption t _1/2, even when this absorption t _1/2 is much less than t _1/2,z, and describe the relevance of this in designing extended release dosage forms. The t _{1/2, op} is compared with previously proposed half-lives for predicting accumulation.