CoChat
Sign Up
Cited by 108Pharmacogenetics and Drug MetabolismPharmaceutical studies and practicesDrug Solubulity and Delivery Systems

The DOI matches its Crossref record; 25 of the 25 references it cites were found in a registry or an index.

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

Open access
Sahin, Selma, Benet, Leslie Z.·2008·Pharmaceutical Research
DOI 10.1007/s11095-008-9787-9PMC PMC3581066
Open this paper in CoChat — free account

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.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1007/s11095-008-9787-9

Cites

25 of 25 references verified0 citation errors · 0 not checkable

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • For certain drugs and/or formulations, such as those with modified release, prolonged absorption, and multicompartment distribution, terminal half-life (t1/2z) may not accurately reflect how long the drug persists in the body or the actual time required to reach steady state.

    “However, for certain drugs and/or formulations, such as those with modified release, prolonged absorption, and multicompartment distribution, t1/2z may not accurately reflect how long the drug persists in the body or the actual time required to reach steady state.”

    From Evaluation of Effective Half-Life and Its Impact on Time to Steady State for Oral MeltDose Tacrolimus (LCPT) in De Novo Kidney Transplant Recipients (2025) · cites this paper as [2]

    The Introduction and Discussion (pages unavailable) explain that multicompartment kinetics, absorption rate, and extended-release formulations can make terminal half-life a poor predictor of accumulation during repeated dosing. But the Discussion says terminal half-life describes drug loss after dosing stops, and the passages do not establish that it misrepresents how long a drug persists in the body or the time required to reach steady state. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 2

  1. L. Z. Benet. Multiple dosing half-life. A composite term useful in designing therapeutic regimens. Presented at The Third Japanese–American Conference on Pharmacokinetics and Biopharmaceutics, Kyoto, Japan (1985), as available through reference 4.
  2. F. H. Dost. Der Blutspiegel. Thieme, Leipzig, 1953, pp. 252–255.

Cited by

Sorted by citations

Related

Metadata

Authors
Sahin, S., & Benet, L. Z.
Affiliations
University of California, San Francisco (US)
Corresponding author
Benet, Leslie Z.
ORCID
Benet, Leslie Z.
Venue
Pharmaceutical Research
Publisher
Springer Science and Business Media LLC
Published
2008-11-18
Volume
25
Issue
12
Pages
2869-2877
ISSN
  • 0724-8741 (ISSN-L)
  • 1573-904X
DOI
10.1007/s11095-008-9787-9
PMC
PMC3581066
OpenAlex
W2043996867
Cited by
108
References
25
Citations by year
2026: 5 · 2025: 8 · 2024: 8 · 2023: 7 · 2022: 15 · 2021: 7 · 2020: 11 · 2019: 4 · 2017: 3 · 2016: 11 · 2015: 1 · 2014: 2 · 2013: 5 · 2012: 4
FWCI
5.16
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Pharmaceutical Research (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Hacettepe University Institutional Repository (hacettepe.edu.tr) (submittedVersion, other-oa)
Funders
National Institute of General Medical Sciences (R21GM075900, R21 GM 75900)
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Drug Solubulity and Delivery Systems
Keywords
drug accumulation, steady-state accumulation, terminal half-life, dosing interval, diazepam, absorption half-life, extended release dosage forms, oral administration
MeSH terms
Delayed-Action Preparations, Half-Life, Humans

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review