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.
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Abbreviations
- AUC:
-
area under the curve
- AUMC:
-
area under the moment curve
- EHL:
-
effective half-life
- MRT:
-
mean residence time in the body
- MRTc :
-
mean residence time in the central compartment
- Rc :
-
Wagner’s drug accumulation index
- sd:
-
single dose
- ss:
-
steady-state
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Acknowledgements
Drs. Sahin and Benet were supported in part during the course of this work by NIH Grant R21 GM75900. The authors appreciate the critical reviews of this work as it progressed and the suggestions of Drs. Malcolm Rowland, Nicholas Holford, Harold Boxenbaum, Svein Øie and Stephen Hwang. Thanks also to Ms. Anita Grover for sharing her preliminary evaluations of everolimus and bepridil simulations with changing absorption rate.
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Sahin, S., Benet, L.Z. The Operational Multiple Dosing Half-life: A Key to Defining Drug Accumulation in Patients and to Designing Extended Release Dosage Forms. Pharm Res 25, 2869–2877 (2008). https://doi.org/10.1007/s11095-008-9787-9
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DOI: https://doi.org/10.1007/s11095-008-9787-9