Ethical, legal, and social implications (ELSI) of microdose clinical trials

Kurihara, Chieko

doi:10.1016/j.addr.2011.01.002

Cited by 9 publications

(13 citation statements)

References 11 publications

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“…It is not clear whether the kinetics of a microdose of a drug in vivo can predict the PK of a much larger therapeutic dose. However, there is mounting evidence that microdosing results are predictive of plasma PK and metabolism at the therapeutic dose level across a wide range of different chemical classes 4, 5 .…”

Section: Introductionmentioning

confidence: 99%

Biphasic Elimination of Tenofovir Diphosphate and Nonlinear Pharmacokinetics of Zidovudine Triphosphate in a Microdosing Study

Chen

Flexner

Liberman

et al. 2012

JAIDS Journal of Acquired Immune Deficiency Syndromes

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Objective Phase 0 studies can provide initial pharmacokinetics (PK) 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 two antiretroviral drugs, zidovudine (ZDV) and tenofovir (TFV), in microdose and standard dosing regimens. Study Design We administered a microdose (100 μg) of 14C-labeled drug (ZDV or tenofovir disoproxil fumarate (TDF)) 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 PBMCs and CD4+ cells were measured by AMS. Results The intracellular ZDV-TP concentration increased less than proportionally over the dose range studied (100 μg to 300 mg), while the intracellular TFV-DP PK were linear over the same dose range. ZDV-TP concentrations were lower in CD4+ cells versus total peripheral blood mononuclear cells (PBMCs), while TFV-DP concentrations were not different in CD4+ cells and PBMCs. Conclusion Our data were consistent with a rate-limiting step in the intracellular phosphorylation of ZDV but not TFV. AMS 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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Section: Introductionmentioning

confidence: 99%

Biphasic Elimination of Tenofovir Diphosphate and Nonlinear Pharmacokinetics of Zidovudine Triphosphate in a Microdosing Study

Chen

Flexner

Liberman

et al. 2012

JAIDS Journal of Acquired Immune Deficiency Syndromes

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“…In addition, phase 0 approaches can lead to reduced use of animals in human drug development 138 . Of course, the potential for increased efficiency of drug development may mean increased health care benefits and increased ethical benefit-risk balance, topics discussed in greater detail elsewhere 33,138,[140][141][142][143] .…”

Section: Operational and Ethical Aspectsmentioning

confidence: 99%

Phase 0/microdosing approaches: time for mainstream application in drug development?

Burt¹,

Young

Lee

et al. 2020

Nat Rev Drug Discov

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Phase 0 approaches-which include microdosing-evaluate subtherapeutic exposures of new drugs in first-inhuman studies known as exploratory clinical trials. Recent progress extends phase 0 benefits beyond assessment of pharmacokinetics to include understanding of mechanism of action and pharmacodynamics. Phase 0 approaches have the potential to improve preclinical candidate selection and enable safer, cheaper, quicker and more informed developmental decisions. Here, we discuss phase 0 methods and applications, highlight their advantages over traditional strategies and address concerns related to extrapolation and developmental timelines. Although challenges remain, we propose that phase 0 approaches be at least considered for application in most drug development scenarios.

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“…The main ethical benefits of the exploratory approaches are in the reduction of risk in human testing, the early identification and rejection of ineffective or toxic compounds, thereby avoiding delays in development of successful back‐up compounds, and preventing unnecessary testing in humans and animals. The ethics of administering drugs to humans with no therapeutic intent was brought up in earlier reports as a challenge to phase 0 studies . However, such testing, no different from usual phase I testing in healthy volunteers where also there is no therapeutic intent, is justified by the scientific necessity and beneficence implied in a more efficient drug development process.…”

Section: Recommendationsmentioning

confidence: 99%

“…The ethics of administering drugs to humans with no therapeutic intent was brought up in earlier reports as a challenge to phase 0 studies. [91][92][93] However, such testing, no different from usual phase I testing in healthy volunteers where also there is no therapeutic intent, is justified by the scientific necessity and beneficence implied in a more efficient drug development process. Phase 0 approaches are also consistent with the 3Rs, reduction, refinement, and replacement, promoting ethical animal research.…”

Section: Ethics -Risk/benefit Assessmentmentioning

confidence: 99%

Microdosing and Other Phase 0 Clinical Trials: Facilitating Translation in Drug Development

Burt¹,

Yoshida

Lappin

et al. 2016

Clinical Translational Sci

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Ethical, legal, and social implications (ELSI) of microdose clinical trials

Cited by 9 publications

References 11 publications

Biphasic Elimination of Tenofovir Diphosphate and Nonlinear Pharmacokinetics of Zidovudine Triphosphate in a Microdosing Study

Biphasic Elimination of Tenofovir Diphosphate and Nonlinear Pharmacokinetics of Zidovudine Triphosphate in a Microdosing Study

Phase 0/microdosing approaches: time for mainstream application in drug development?

Microdosing and Other Phase 0 Clinical Trials: Facilitating Translation in Drug Development

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