ArticlePharmaceutical research2008
The operational multiple dosing half-life: a key to defining drug accumulation in patients and to designing extended release dosage forms.
Article in Pharmaceutical research, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
46 citing papers in PubMed, 1 synthesis or guideline pooled it.
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- Safety, tolerability, and pharmacokinetics of repeated oral doses of 2-hydroxybenzylamine acetate in healthy volunteers: a double-blind, randomized, placebo-controlled clinical trial.BMC pharmacology & toxicology · 2020Trial
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- No Interference of H9 Extract on Trastuzumab Pharmacokinetics in Their Combinations.International journal of molecular sciences · 2023Article
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- In vivo degradation forms, anti-degradation strategies, and clinical applications of therapeutic peptides in non-infectious chronic diseases.European journal of pharmacology · 2022Review
- Current Approaches for Predicting Human PK for Small Molecule Development Candidates: Findings from the IQ Human PK Prediction Working Group Survey.The AAPS journal · 2022Review
- Clinical Pharmacokinetic Assessment of Kratom (Pharmaceutics · 2022Article
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Corrections and comments
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Authors and funding
2 authors.
Funding
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 (1/2)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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Registered trials
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