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Pharm Res. 2008 Dec;25(12):2869-77. doi: 10.1007/s11095-008-9787-9. Epub 2008 Nov 18.

The operational multiple dosing half-life: a key to defining drug accumulation in patients and to designing extended release dosage forms.

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Department of Biopharmaceutical Sciences, University of California, San Francisco, CA 94143-0912, USA.


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 (1/2)s 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.

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