Accelerator Mass Spectrometry-Enabled Studies: Current Status and Future Prospects

Arjomand, Ali

doi:10.4155/bio.09.188

Cited by 30 publications

(20 citation statements)

References 142 publications

(90 reference statements)

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“…This technique relies on determination of the 14 C/ 12 C isotope ratio [46,47] and can be up to a millionfold more sensitive than LSC [48]. Since the first publication of a biomedical application of AMS in 1990 [49], the technique has extensively been reviewed in literature [50][51][52] and also its application in human mass balance studies has been the subject of recent reviews [1,53]. From the recent mass balance studies in oncology listed in Table 1, four used AMS to calculate the total amount of drug-related 14 C in at least part of the samples.…”

Section: Analysis Of Total Radioactivitymentioning

confidence: 99%

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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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Section: Analysis Of Total Radioactivitymentioning

confidence: 99%

“…To date, wide application of AMS is still hampered by the high costs of the instrument. Other disadvantages of AMS include the complexity of the method and sample preparation procedures that are not amenable for automation [50].…”

Section: Analysis Of Total Radioactivitymentioning

confidence: 99%

Bioanalytical Aspects of Clinical Mass Balance Studies in Oncology

Dubbelman¹,

Rosing

Schellens

et al. 2011

Bioanalysis

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“…Carbon can thus be dated radiometrically by quantifying the amount of 14 C, yielding an estimated age of an organic substance (Vogel et al, 1995;Hah et al, 2009). AMS has frequently been used in environmental research, the exploration of natural resources, earth sciences, and the investigation of natural materials (Arjomand, 2010). AMS can quantify such elements (isotopes) as 10 Be, 14 C, 26 Al, 36 Cl, 41 Ca, and 129 I in addition to the target isotope, 14 C, and its measurement accuracy can be secured within a tolerance of the measurement error at units of 10 −12 to 10 −18 (Budzikiewicz and Grigsby, 2006).…”

Section: Analytical Technology Of Amsmentioning

confidence: 99%

“…For 14 C quantification assays, samples should be subjected to a highly purified graphitization process in which the human bodily fluid is combusted. Various pretreatment protocols are required before AMS analysis, depending on the necessity of sample drying or reduction (Kim et al, 2008(Kim et al, , 2010Arjomand, 2010;Salehpour et al, 2010). These processes involve unique manipulations that have been developed according to the pretreatment technology available at a given institution.…”

Section: Microdosing Studies Based On Amsmentioning

confidence: 99%

Microdosing studies using accelerated mass spectrometry as exploratory investigational new drug trials

Bae

Shon

2011

Arch. Pharm. Res.

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Innovative attempts have been made to overcome nonproductivity and high expenditure in the clinical stages of new drug development. Microdosing studies using subpharmacological doses provide early insight into the body's disposition toward candidate compounds, and are innovative exploratory trials that can promote productivity in drug development. Highly sensitive analytical technology is crucial in microdosing studies that employ qualitative and quantitative assays of target materials in humans. Accelerator mass spectrometry (AMS) has facilitated the adoption of a human microdosing study in the early phase of clinical drug development. Results derived from AMS microdosing studies using labeled compounds can provide various types of information for candidate selection, including pharmacokinetic characteristics and metabolic profiles of candidate compounds. The applicability of microdosing studies is currently expanding into absolute bioavailability and mass balance studies. Although it remains uncertain whether microdosing adequately predicts the pharmacokinetics of therapeutic doses, further development of microdosing studies using AMS may benefit the field of new drug development and could pose a new challenge to researchers. The use of advanced technology in candidate selection will contribute to improved productivity and competitiveness in pharmaceutical research and development. The introduction of microdosing studies using AMS in Korea will present a newly applicable method for innovative clinical trials and contribute to development potential in global competition.

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“…AMS can deliver analytical sensitivity far in excess of most other tools and has been applied to the preclinical and clinical mass balance studies [4,54]. The radiation risk, therefore, is not a concern for the study using AMS due to its low radioactive dose (tracer) and dosimetry data are not required.…”

Section: Human Mass Balance Studiesmentioning

confidence: 99%

Mass Balance Studies in Animals and Humans

Lin¹,

Heimbach²,

Gollen³

et al. 2012

Encyclopedia of Drug Metabolism and Interactions

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Before first‐in‐human (FIH) studies with a new drug candidate, preclinical studies need to be conducted to fulfill regulatory requirements or to facilitate regulatory approval. In the United States, investigational new drug (IND) applications with the Food and Drug Administration (FDA) may include IND enabling studies, such as (i) in vitro and in vivo pharmacology studies for intended use, (ii) toxicology studies supporting the starting dose and duration of an FIH study (such as single‐ or multiple‐dose studies in one rodent and nonrodent species with toxicokinetics, genotoxicity battery, safety pharmacology battery), (iii) single‐dose pharmacokinetics (PKs) in one rodent and nonrodent species, (iv) in vitro plasma protein binding in relevant species, and (v) in vitro cross species metabolism study in relevant species. While not mandatory for IND submissions, comprehensive preclinical absorption, distribution, metabolism, and excretion (ADME) studies, including biotransformation or metabolite profiling, conventional mass balance, or tissue distribution by quantitative whole‐body autoradiography (QWBA) studies can make a submission package more compelling for progression toward phase I clinical studies. Typically, preclinical ADME together with mass balance studies are recommended before conducting human ADME and mass balance studies, which are generally initiated after the successful synthesis of the radiolabeled drug. For preclinical ADME species, the selection of doses is often based on pre‐existing toxicity information and targeted therapeutic doses. For human ADME studies, which include the evaluation of mass balance, a relevant dose in the anticipated therapeutic range is typically chosen. Conventional mass balance studies only allow the calculation of mass recovery and PK parameters of the radiolabeled drug by quantification of the radioactivity present in excreta such as urine, feces, or bile. Nowadays, these mass balance studies are often conducted as part of more comprehensive ADME studies, where additional information is obtained, including (i) PK properties of the drug and its metabolite(s) in blood or plasma; (ii) absorption estimates via plasma/blood data, urinary data, or fecal data; (iii) elimination pathways and drug metabolism; (iv) total drug exposure and its metabolites in different organs and tissues at different time intervals. In this chapter, fundamental scientific considerations for the successful design, conduct, and interpretation of conventional, basic mass balance and more comprehensive ADME studies are reviewed and discussed.

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Accelerator Mass Spectrometry-Enabled Studies: Current Status and Future Prospects

Cited by 30 publications

References 142 publications

Bioanalytical Aspects of Clinical Mass Balance Studies in Oncology

Bioanalytical Aspects of Clinical Mass Balance Studies in Oncology

Microdosing studies using accelerated mass spectrometry as exploratory investigational new drug trials

Mass Balance Studies in Animals and Humans

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