Trial reportJournal of acquired immune deficiency syndromes (1999)2012
Biphasic elimination of tenofovir diphosphate and nonlinear pharmacokinetics of zidovudine triphosphate in a microdosing study.
Trial report in Journal of acquired immune deficiency syndromes (1999), 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
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.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
19 citing papers in PubMed, 2 citations in OpenAlex.
- Dose Frequency Ranging Pharmacokinetic Study of Tenofovir-Emtricitabine After Directly Observed Dosing in Healthy Volunteers to Establish Adherence Benchmarks (HPTN 066).AIDS research and human retroviruses · 2016Trial
- Population pharmacokinetics of tenofovir and tenofovir-diphosphate in healthy women.Journal of clinical pharmacology · 2015Trial
- Single dose pharmacokinetics of oral tenofovir in plasma, peripheral blood mononuclear cells, colonic tissue, and vaginal tissue.AIDS research and human retroviruses · 2013Trial
- Pharmacogenomics of Antiretroviral Drug Metabolism and Transport.Annual review of pharmacology and toxicology · 2021Review
- Phase 0/microdosing approaches: time for mainstream application in drug development?Nature reviews. Drug discovery · 2020Review
- Long-acting approaches for delivery of antiretroviral drugs for prevention and treatment of HIV: a review of recent research.Expert opinion on drug delivery · 2020Review
- Feasibility of Short-Term PrEP Uptake for Men Who Have Sex With Men With Episodic Periods of Increased HIV Risk.Journal of acquired immune deficiency syndromes (1999) · 2020Article
- Direct and indirect quantification of phosphate metabolites of nucleoside analogs in biological samples.Journal of pharmaceutical and biomedical analysis · 2020Review
- Long-acting implants to treat and prevent HIV infection.Current opinion in HIV and AIDS · 2020Article
- Predictive Value of Microdose Pharmacokinetics.Clinical pharmacokinetics · 2019Review
- HIV Antiretroviral Pre-Exposure Prophylaxis: Development Challenges and Pipeline Promise.Clinical pharmacology and therapeutics · 2018Article
- Universal antiretroviral regimens: thinking beyond one-pill-once-a-day.Current opinion in HIV and AIDS · 2017Review
- Use of microdosing and accelerator mass spectrometry to evaluate the pharmacokinetic linearity of a novel tricyclic GyrB/ParE inhibitor in rats.Antimicrobial agents and chemotherapy · 2014Article
- Preferences for daily or intermittent pre-exposure prophylaxis regimens and ability to anticipate sex among HIV uninfected members of Kenyan HIV serodiscordant couples.AIDS and behavior · 2014Article
- Tenofovir diphosphate concentrations and prophylactic effect in a macaque model of rectal simian HIV transmission.The Journal of antimicrobial chemotherapy · 2014Article
- Sex hormones regulate tenofovir-diphosphate in female reproductive tract cells in culture.PloS one · 2014Article
- Intravaginal ring eluting tenofovir disoproxil fumarate completely protects macaques from multiple vaginal simian-HIV challenges.Proceedings of the National Academy of Sciences of the United States of America · 2013Article
- Microdosing and drug development: past, present and future.Expert opinion on drug metabolism & toxicology · 2013Review
- Intracellular Tenofovir and Emtricitabine Anabolites in Genital, Rectal, and Blood Compartments from First Dose to Steady State.AIDS research and human retrovirusesObservational
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
objectivePhase 0 studies can provide initial pharmacokinetics (PKs) data in humans and help to facilitate early drug development, but their predictive value for standard dosing is controversial. To evaluate the prediction of microdosing for active intracellular drug metabolites, we compared the PK profile of 2 antiretroviral drugs, zidovudine (ZDV) and tenofovir (TFV), in microdose and standard dosing regimens. STUDY
designWe administered a microdose (100 μg) of C-labeled drug (ZDV or tenofovir disoproxil fumarate) with or without a standard unlabelled dose (300 mg) to healthy volunteers. Both the parent drug in plasma and the active metabolite, ZDV-triphosphate (ZDV-TP) or TFV-diphosphate (TFV-DP) in peripheral blood mononuclear cells (PBMCs) and CD4 cells were measured by accelerator mass spectrometry.
resultsThe intracellular ZDV-TP concentration increased less than proportionally over the dose range studied (100 μg-300 mg), whereas the intracellular TFV-DP PKs were linear over the same dose range. ZDV-TP concentrations were lower in CD4 cells versus total PBMCs, whereas TFV-DP concentrations were not different in CD4 cells and PBMCs.
conclusionsOur data were consistent with a rate-limiting step in the intracellular phosphorylation of ZDV but not TFV. Accelerator mass spectrometry shows promise for predicting the PK of active intracellular metabolites of nucleosides, but nonlinearity of PK may be seen with some drugs.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.