A validation study comparing accelerator MS and liquid scintillation counting for analysis of 14C-labelled drugs in plasma, urine and faecal extracts

Garner, R. Colin; Barker, James; Flavell, C; Garner, John; Whattam, M.; Young, Graeme; Cussans, Nigel J.; Jezequel, S. G.; Leong, David Tai

doi:10.1016/s0731-7085(00)00397-6

Cited by 63 publications

(44 citation statements)

References 14 publications

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“…at ASPET Journals on May 12, 2018 dmd.aspetjournals.org sources of 14 C. However, when appropriate procedures are put in place, excellent concordance can be obtained between measurements conducted by AMS and LSC (Kaye et al, 1997;Garner et al, 2000;Young et al, 2001). In the present study, plasma levels of unchanged Compound A after a 1 mg/kg oral dose, measured by a specific LC-MS/MS assay, proved to be closely similar to those of total 14 C assessed by AMS.…”

Section: Evaluation Of Microdosing Strategiessupporting

confidence: 74%

Evaluation of Microdosing Strategies for Studies in Preclinical Drug Development: Demonstration of Linear Pharmacokinetics in Dogs of a Nucleoside Analog Over a 50-Fold Dose Range

Sandhu¹,

Vogel²,

Rose³

et al. 2004

Drug Metab Dispos

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ABSTRACT:The technique of accelerator mass spectrometry (AMS) was validated successfully and used to study the pharmacokinetics and disposition in dogs of a preclinical drug candidate (7-deaza-2-Cmethyl-adenosine; Compound A), after oral and intravenous administration. The primary objective of this study was to examine whether Compound A displayed linear kinetics across subpharmacological (microdose) and pharmacological dose ranges in an animal model, before initiation of a human microdose study. The AMS-derived disposition properties of Compound A were comparable to data obtained via conventional techniques such as liquid chromatography-tandem mass spectrometry and liquid scintillation counting analyses. Compound A displayed multiphasic kinetics and exhibited low plasma clearance (5.8 ml/min/kg), a long terminal elimination half-life (17.5 h), and high oral bioavailability (103%). Currently, there are no published comparisons of the kinetics of a pharmaceutical compound at pharmacological versus subpharmacological doses using microdosing strategies. The present study thus provides the first description of the full pharmacokinetic profile of a drug candidate assessed under these two dosing regimens. The data demonstrated that the pharmacokinetic properties of Compound A following dosing at 0.02 mg/kg were similar to those at 1 mg/kg, indicating that in the case of Compound A, the pharmacokinetics in the dog appear to be linear across this 50-fold dose range. Moreover, the exceptional sensitivity of AMS provided a pharmacokinetic profile of Compound A, even after a microdose, which revealed aspects of the disposition of this agent that were inaccessible by conventional techniques.The applications of accelerator mass spectrometry (AMS) are broad-ranging and vary from studying environmental and ecological issues such as the isotopic composition of the atmosphere, soil, and water (Hughen et al., 2000;Beck et al., 2001;Keith-Roach et al., 2001;Mironov et al., 2002), to archaeology and volcanology (Stafford et al., 1984;Vogel et al., 1990;Smith et al., 1999), to its use as a bioanalytical tool for nutritional research (Buchholz et al., 1999; Deuker et al., 2000;Weaver and Liebman, 2002). Biomedical applications of AMS and its use in the arena of pharmaceutical research also have been detailed in review articles (Barker and Garner, 1999;Garner, 2000;Turteltaub and Vogel, 2000). To date, most studies on the metabolism and disposition of xenobiotics by AMS have focused on the binding of carcinogens to DNA and proteins (Turteltaub et al., 1990Frantz et al., 1995;Dingley et al., 1999;Li et al., 2003). These studies have demonstrated a linear relationship between dose and DNA adduct formation. Applications of AMS to the field of pharmaceutical sciences have been limited to only a few studies (Kaye et al., 1997;Young et al., 2001;Garner et al., 2002). However, the pharmaceutical industry is becoming increasingly aware of the potential benefits that may accrue from the ultra-high sensitivity afforded by AMS in terms of evalu...

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Section: Evaluation Of Microdosing Strategiessupporting

confidence: 74%

Evaluation of Microdosing Strategies for Studies in Preclinical Drug Development: Demonstration of Linear Pharmacokinetics in Dogs of a Nucleoside Analog Over a 50-Fold Dose Range

Sandhu¹,

Vogel²,

Rose³

et al. 2004

Drug Metab Dispos

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“…The concentration of drug-derived 14 C radioactivity in individual plasma samples was determined by AMS at Accium Biosciences (Seattle, WA). A detailed procedure describing the use of AMS for this purpose has been described previously (Garner et al, 2000). Portions of each of the plasma pharmacokinetic samples were converted to graphite in a two-step process involving oxidation to carbon dioxide followed by reduction (Vogel, 1992).…”

Section: Chemicals [mentioning

confidence: 99%

Metabolism and Disposition of [¹⁴C]BMS-690514, an ErbB/Vascular Endothelial Growth Factor Receptor Inhibitor, after Oral Administration to Humans

Christopher¹,

Hong²,

Vakkalagadda³

et al. 2010

Drug Metab Dispos

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(3R,4R)-4-Amino-1-((4-((3-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)methyl)-3-piperidinol (BMS-690514), an oral selective inhibitor of human epidermal growth factor receptors 1 (or epidermal growth factor receptor), 2, and 4, and vascular endothelial growth factor receptors 1, 2, and 3, is being developed as a treatment for patients with non-small-cell lung cancer and metastatic breast cancer. The disposition of [ 14 C]BMS-690514 was investigated in nine healthy male subjects (group 1, n ‫؍‬ 6; group 2, n ‫؍‬ 3) after oral administration of a 200-mg dose. Urine, feces, and plasma were collected from all subjects for up to 12 days postdose. In group 2 subjects, bile was collected from 3 to 8 h postdose. Across groups, approximately 50 and 34% of administered radioactivity was recovered in the feces and urine, respectively. An additional 16% was recovered in the bile of group 2 subjects. Less than 28% of the dose was recovered as parent drug in the combined excreta, suggesting that BMS-690514 was highly metabolized. BMS-690514 was rapidly absorbed (median time of maximum observed concentration 0.5 h) with the absorbed fraction estimated to be approximately 50 to 68%. BMS-690514 represented <7.9% of the area under the concentration-time curve from time 0 extrapolated to infinite time of plasma radioactivity, indicating that the majority of the circulating radioactivity was from metabolites. BMS-690514 was metabolized via multiple oxidation reactions and direct glucuronidation. Circulating metabolites included a hydroxylated rearrangement product (M1), a direct ether glucuronide (M6), and multiple secondary glucuronide conjugates. None of these metabolites is expected to contribute to the pharmacology of BMS-690514. In summary, BMS-690514 was well absorbed and extensively metabolized via multiple metabolic pathways in humans, with excretion of drug-related radioactivity in both bile and urine.

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“…The reason for this observation is not clear at this point and it may be due to the low-level contamination in sample preparation as mentioned in the 'Instrument qualification for direct MICADAS-cAMS analysis' section. Once these sample preparation issues have been addressed, MICADAS-cAMS quantification at the later time points might be more accurate due to the superior sensitivity (atom counting 14 C) for AMS versus decay counting for liquid scintillation technologies [20,23] and better precision of MICADAS-cAMS over LSC [24]. This would lead to a better estimation of the terminal half-life of the compound in the Group 2 ( Figure 1).…”

Section: Pk Of Radioactivitymentioning

confidence: 99%

“…In the present study, we evaluate the direct measurement of sample CO 2 (cAMS) combined with MICADAS (MICADAS-cAMS) for ADME studies. Whenever possible, our investigations follow previous recommendations [8,12,20] on critical bioanalysis parameters needed to perform adequate radioactivity quantification in the scope of an ADME study.…”

mentioning

confidence: 90%

Evaluation of cAMS for ¹⁴ C Microtracer ADME Studies: Opportunities to Change the Current Drug Development Paradigm

Lozac'h

Fahrni²,

Maria

et al. 2018

Bioanalysis

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Aim:Although regulatory guidances require human metabolism information of drug candidates early in the development process, the human mass balance study (or hADME study), is performed relatively late. hADME studies typically involve the administration of a 14 C-radiolabelled drug where biological samples are measured by conventional scintillation counting analysis. Another approach is the administration of therapeutic doses containing a 14 C-microtracer followed by accelerator mass spectrometry (AMS) analysis, enabling hADME studies completion much earlier. Consequently, there is an opportunity to change the current drug development paradigm. Materials & methods: To evaluate the applicability of the MICADAScAMS method, we successfully performed: the validation of MICADAS-cAMS for radioactivity quantification in biomatrices and, a rat ADME study, where the conventional methodology was assessed against a microtracer MICADAS-cAMS approach. Results & discussion: Combustion AMS (cAMS) technology is applicable to microtracer studies. A favorable opinion from EMA to complete the hADME in a Phase I setting was received, opening the possibilities to change drug development. Keywords:In the scope of drug development, regulatory guidances encourage the early identification of relevant human metabolites [1][2][3]. A human ADME study that used radiolabeled drugs allows the identification of metabolites and the elucidation of key biotransformation pathways and clearance mechanisms in humans. However, due to the high study cost, the needs for a dosimetry assessment (which include a rat distribution investigation) and for a GMP manufacturing as well as the high attrition rates encountered in drug development, the conventional hADME is generally performed late in drug development (Phase II, see Supplementary Figure 1). The administered dose in a conventional hADME study can contain up to 3.7 mBq of radioactivity which is analysed by scintillation counting. To address the regulatory demands earlier, a first investigation of pharmacokinetics (PK) and excretion routes is typically performed with a radiolabeled drug in rodents. Subsequently, exploratory analysis of potentially relevant metabolites is investigated in early clinical samples (Phase I) without the use of radiolabel [4,5] (Supplementary Figure 1). However, the applied LC-MS methods can fail to identify unknown metabolites. If human-specific metabolites are generated in early clinical samples, these metabolites will not be detected in preclinical species using radiolabeled drug, and will not be discovered in humans until the radiolabeled human mass balance ADME study is completed. To address this gap, we propose to dose a normal, therapeutically relevant dose spiked with very low amounts of a radiotracer to healthy volunteers or patients in a Phase I setting. Thereafter, the mass balance, the excretion routes and levels of circulating metabolites in humans are determined by accelerator mass spectrometry (AMS) as suggested by Lappin and Garner [6,7].AMS is a highly sensit...

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A validation study comparing accelerator MS and liquid scintillation counting for analysis of 14C-labelled drugs in plasma, urine and faecal extracts

Cited by 63 publications

References 14 publications

Evaluation of Microdosing Strategies for Studies in Preclinical Drug Development: Demonstration of Linear Pharmacokinetics in Dogs of a Nucleoside Analog Over a 50-Fold Dose Range

Evaluation of Microdosing Strategies for Studies in Preclinical Drug Development: Demonstration of Linear Pharmacokinetics in Dogs of a Nucleoside Analog Over a 50-Fold Dose Range

Metabolism and Disposition of [¹⁴C]BMS-690514, an ErbB/Vascular Endothelial Growth Factor Receptor Inhibitor, after Oral Administration to Humans

Evaluation of cAMS for ¹⁴ C Microtracer ADME Studies: Opportunities to Change the Current Drug Development Paradigm

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A validation study comparing accelerator MS and liquid scintillation counting for analysis of 14C-labelled drugs in plasma, urine and faecal extracts

Cited by 63 publications

References 14 publications

Evaluation of Microdosing Strategies for Studies in Preclinical Drug Development: Demonstration of Linear Pharmacokinetics in Dogs of a Nucleoside Analog Over a 50-Fold Dose Range

Evaluation of Microdosing Strategies for Studies in Preclinical Drug Development: Demonstration of Linear Pharmacokinetics in Dogs of a Nucleoside Analog Over a 50-Fold Dose Range

Metabolism and Disposition of [14C]BMS-690514, an ErbB/Vascular Endothelial Growth Factor Receptor Inhibitor, after Oral Administration to Humans

Evaluation of cAMS for 14 C Microtracer ADME Studies: Opportunities to Change the Current Drug Development Paradigm

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Product

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Metabolism and Disposition of [¹⁴C]BMS-690514, an ErbB/Vascular Endothelial Growth Factor Receptor Inhibitor, after Oral Administration to Humans

Evaluation of cAMS for ¹⁴ C Microtracer ADME Studies: Opportunities to Change the Current Drug Development Paradigm