Microdose Study of 14C-Acetaminophen With Accelerator Mass Spectrometry to Examine Pharmacokinetics of Parent Drug and Metabolites in Healthy Subjects

Tozuka, Zenzaburo; Kusuhara, Hiroyuki; Nozawa, Kohei; Hamabe, Y.; Ikushima, Ichiro; Ikeda, Toshihiko; Sugiyama, Yuichi

doi:10.1038/clpt.2010.206

Cited by 36 publications

(22 citation statements)

References 20 publications

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“…In addition, although many comparative studies for various drugs have shown PK linearity between the micro-dose and therapeutic dose [25-28], micro-dosing studies may not always accurately predict the PK parameters at higher therapeutic doses [29-31]. This non-linearity may arise from the non-linear disposition of a drug as well as the saturation of metabolic enzymes or drug transporters [32,33].…”

Section: Discussionmentioning

confidence: 99%

Dose selection method for pharmacokinetic study in hemodialysis patients using a subpharmacological dose: oseltamivir as a model drug

et al. 2014

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BackgroundDose selection is an important step in pharmacokinetic (PK) studies of hemodialysis patients. We propose a simulation-based dose-selection method for PK studies of hemodialysis patients using a subpharmacological dose of oseltamivir as a model drug.MethodsThe concentrations of oseltamivir and its active metabolite, oseltamivir carboxylate (OC), were measured by liquid chromatography-tandem mass spectrometry. To determine a low oseltamivir dose exhibiting PK linearity, a pilot low dose determination investigation (n = 4) was performed using a single administration dose-escalation study. After the dose was determined, a low dose study (n = 10) was performed, and the optimal dose required to reach the hypothetical target OC exposure (area under the concentration-time curve [AUC] of 60,000 ng · hr/mL) was simulated using a nonparametric superposition method. Finally, observed PKs at the optimal dose were compared to the simulated PKs to verify PK predictability.ResultsIn the pilot low dose determination study, 2.5 mg of oseltamivir was determined to be the low dose. Subsequently, we performed a single-dose PK study with the low oseltamivir dose in an additional group of 10 hemodialysis patients. The predicted AUClast of OC following continuous oseltamivir doses was simulated, and 35 mg of oseltamivir corresponded to the hypothetical target AUClast of OC. The observed PK profiles of OC at a 35-mg oseltamivir dose and the simulated data based on the low dose study were in close alignment.ConclusionThe results indicate that the proposed method provides a rational approach to determine the proper PK dose in hemodialysis patients.

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Section: Discussionmentioning

confidence: 99%

Dose selection method for pharmacokinetic study in hemodialysis patients using a subpharmacological dose: oseltamivir as a model drug

et al. 2014

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“…In this type of study, a microdose of an investigational drug with a radioactivity in the nCi range is administered to humans, and the highly sensitive technique AMS is used to quantify the low concentrations of total radioactivity and (in combination with HPLC) to produce radiochromatograms for metabolite profiling [50,53,68,69]. However, the costs, size and complexity of AMS will have to be reduced to make wide application possible.…”

Section: Future Perspectivementioning

confidence: 98%

Bioanalytical Aspects of Clinical Mass Balance Studies in Oncology

Dubbelman¹,

Rosing

Schellens

et al. 2011

Bioanalysis

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Clinical mass balance studies aim to investigate the absorption, distribution, metabolism and excretion (ADME) of a(n) (often radiolabeled) drug, following a single administration to humans. They are perfectly suited to determine the disposition and major metabolic pathways of a drug, the exposure to the parent drug and its metabolites, and the rate and route of elimination. A mass balance study, however, poses interesting challenges to the analysis of parent drug and metabolites in different biological matrices. Using recent clinical mass balance studies in oncology as an example, this review focuses on the aspects of mass balance studies, from bioanalytical assay development, analysis of clinical samples to reporting of study results. Along the way, it discusses bioanalytical problems and practical solutions.

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“…A review of these studies was published in 2010. 35 Sugiyama and his colleagues have published a number of papers on the linearity question 32,33,[36][37][38] and have endeavoured to predict using in vitro methods such as K m measurement which drugs might deviate from linearity. 39 A commentary around the issues of linearity and the utility of microdosing has been published by Rowland.…”

Section: Scientic Considerationsmentioning

confidence: 99%

Human Microdosing/Phase 0 Studies to Accelerate Drug Development

Garner¹

2014

Human-Based Systems for Translational Research

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There is an urgent need to accelerate the development of new drugs to treat unmet medical needs both in the developed and underdeveloped parts of the world. There is also an urgent need to improve the efficiency of drug development through time and cost reduction because development costs hinder the introduction of new therapies. There are many life-threatening human diseases that still require better therapies including cancer, bacterial and viral infection and lifestyle-associated diseases. The costs of bringing a drug to market are so high that there are very few organisations able to afford to discover, develop and introduce drugs on their own. Estimates of drug development costs vary between US$1.2 and 12.0 billion dollars, making the costs of newly approved drugs very high in order that companies can recover the costs of all the failed drugs in their pipelines. 1,2 It has been estimated that only three out of 10 drugs make a return on their investment and that over 99% of molecules researched by a pharmaceutical company are likely to fail at some point during the development process. 3 Even when a drug enters into RSC Drug Discovery Series No. 41 Human-based Systems for Translational Research Edited by Robert Coleman

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Microdose Study of 14C-Acetaminophen With Accelerator Mass Spectrometry to Examine Pharmacokinetics of Parent Drug and Metabolites in Healthy Subjects

Cited by 36 publications

References 20 publications

Dose selection method for pharmacokinetic study in hemodialysis patients using a subpharmacological dose: oseltamivir as a model drug

Dose selection method for pharmacokinetic study in hemodialysis patients using a subpharmacological dose: oseltamivir as a model drug

Bioanalytical Aspects of Clinical Mass Balance Studies in Oncology

Human Microdosing/Phase 0 Studies to Accelerate Drug Development

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