In a number of cases, well accepted and generally used approaches are just wrong. Here we point out that although the relevance may be understood, the actual value reported for many drugs is not the relevant half-life and that even today the appropriate method for determining the relevant half-life has not been adequately discussed in the literature.
Half-life is the oldest pharmacokinetic parameter and all clinicians believe they understand its relevance.
The t 1/2, op is compared with previously proposed half-lives for predicting accumulation. 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. 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. 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. 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. However, accumulation at steady state may be markedly over predicted utilizing t 1/2, z. Alternatively, terminal half-life ( t 1/2,z) is utilized as the single defining t 1/2 for most drugs. 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.
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