High-performance liquid chromatography accelerator mass spectrometry: Correcting for losses during analysis by internal standardization

Lappin, Graham; Simpson, Marie; Shishikura, Yoko; Garner, Colin

doi:10.1016/j.ab.2008.03.026

Cited by 24 publications

(12 citation statements)

References 7 publications

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“…Resolution of compounds for AMS analysis relies entirely upon the chromatographic separation, which may demand, for example, two-dimensional HPLC, to be confident of complete separation of a target analyte from a mixture where other unknown interfering compounds could be present [40]. In addition, AMS analysis involves a degree of sample processing to form graphite after chromatographic separation, which also demands the accurate addition of an isotopic dilutor [41]. This coupled to the limited number of suitable AMS instruments, with GlaxoSmithKline being the only pharmaceutical company currently with its own AMS facility [42] and LC-MS can often be a winning pragmatic choice.…”

Section: Analytical Methods Associated With Microdosingmentioning

confidence: 99%

Microdosing and drug development: past, present and future

Lappin

Noveck²,

Burt

2013

Expert Opinion on Drug Metabolism & Toxicology

115

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Introduction Microdosing is an approach to early drug development where exploratory pharmacokinetic data are acquired in humans using inherently safe sub-pharmacologic doses of drug. The first publication of microdose data was 10 years ago and this review comprehensively explores the microdose concept from conception, over the past decade, up until the current date. Areas covered The authors define and distinguish the concept of microdosing from similar approaches. The authors review the ability of microdosing to provide exploratory pharmacokinetics (concentration-time data) but exclude microdosing using positron emission tomography. The article provides a comprehensive review of data within the peer-reviewed literature as well as the latest applications and a look into the future, towards where microdosing may be headed. Expert opinion Evidence so far suggests that microdosing may be a better predictive tool of human pharmacokinetics than alternative methods and combination with physiologically based modelling may lead to much more reliable predictions in the future. The concept has also been applied to drug-drug interactions, polymorphism and assessing drug concentrations over time at its site of action. Microdosing may yet have more to offer in unanticipated directions and provide benefits that have not been fully realised to date.

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Section: Analytical Methods Associated With Microdosingmentioning

confidence: 99%

Microdosing and drug development: past, present and future

Lappin

Noveck²,

Burt

2013

Expert Opinion on Drug Metabolism & Toxicology

115

View full text Add to dashboard Cite

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“…For the oral dose, blood samples were obtained prior to dosing (0 hours, predose) and at 0.5, 0.75, 1,2,3,4,6,8,12,16,24,48,72,96,120,144, and 168 hours postdose. For the IV dose, blood samples were obtained prior to dosing (0 hours, predose), at 15 minutes (infusion midpoint) and 30 minutes (end of infusion), and then at 35 minutes, 40 minutes, 45 minutes, and 1, 1.5, 2, 3,4,6,8,12,16,24,48,72,96,120,144, and 168 hours after the start of infusion. Blood samples were collected into Vacutainer tubes containing sodium heparin as anticoagulant at the time points specified above.…”

Section: Pharmacokinetic Samplingmentioning

confidence: 99%

“…7 The concentration of [ 14 C]-related species in each sample was determined by way of a calibration curve. 8 The x-axis ranged from 0.0135 to 12.6288 dpm/mL for IDX899 and from 0.0144 to 14.2029 dpm/mL for IDX989. The lower limit of quantitation taken at the lowest standard in the calibration curve was equivalent to 0.0059 ng/mL for IDX899 and 0.0067 ng/mL for IDX989, respectively.…”

Section: Sample Analysismentioning

confidence: 99%

Microdose Pharmacokinetics of IDX899 and IDX989, Candidate HIV‐1 Non‐Nucleoside Reverse Transcriptase Inhibitors, Following Oral and Intravenous Administration in Healthy Male Subjects

Zhou

Garner

Nicholson

et al. 2009

The Journal of Clinical Pharma

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IDX899 and IDX989 are new non-nucleoside reverse-transcriptase inhibitors (NNRTIs) that exhibit potent inhibition of HIV-1 replication, including NNRTI-resistant mutants. This microdose study investigates the pharmacokinetics and determined oral bioavailability. For each compound, 4 healthy male subjects are randomized to receive via a crossover design a single 100-microg oral and intravenous dose together with 100 nCi of [(14)C]-labeled drug. Plasma and urine samples are obtained over a period of 168 hours postdose and analyzed for total, unchanged drug and major metabolites using an accelerator mass spectrometry method. Based on total radioactivity, oral absorption is near complete. For the parent drug, mean absolute bioavailability is 61% and 65% for IDX899 and IDX989, respectively. Both compounds are extensively metabolized especially after oral dosing. Observed terminal phase half-lives after oral and intravenous doses range from 4 to 10 hours and are comparable for the 2 compounds. Urine excretion of radioactivity for both compounds is less than 10%. These data show for the first time that IDX899 and IDX989 possess favorable pharmacokinetic properties in humans, including high mean absolute bioavailability and long half-life. IDX899 has been selected based on these initial pharmacokinetic assessments and other criteria as the candidate for further clinical development.

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“…This amount is too small to affect the isotopic ratio of the composite sample (as the sample mass is 1 mg). The recovery of the analyte in the protein precipitation step was evaluated by integrating the peak area of the added unlabeled remoxiprid from the HPLC UV detector output over the elution time 14. The values were compared with three aqueous standard solutions of remoxiprid ranging from 0.5 to 2 µM and the recovery was determined.…”

Section: Methodsmentioning

confidence: 99%

FemtoMolar measurements using accelerator mass spectrometry

Salehpour

Forsgard

Possnert

2009

Rapid Comm Mass Spectrometry

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Accelerator mass spectrometry (AMS) is an ultra-sensitive analytical method suitable for the detection of sub-nM concentrations of labeled biological substances such as pharmaceutical drugs in body fluids. A limiting factor in extending the concentration measurements to the sub-pM range is the natural (14)C content in living tissues. This was circumvented by separating the labeled drug from the tissue matrix, using standard high-performance liquid chromatography (HPLC) procedures. As the separated total drug amount is in the few fg range, it is not possible to use a standard AMS sample preparation method, where mg sizes are required. We have utilized a sensitive carbon carrier method where a (14)C-deficient compound is added to the HPLC fractions and the composite sample is prepared and analyzed by AMS. Using 50 microL human blood plasma aliquots, we have demonstrated concentration measurements below 20 fM, containing sub-amol amounts of the labeled drug. The method has the immediate potential of operating in the sub-fM region.

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High-performance liquid chromatography accelerator mass spectrometry: Correcting for losses during analysis by internal standardization

Cited by 24 publications

References 7 publications

Microdosing and drug development: past, present and future

Microdosing and drug development: past, present and future

Microdose Pharmacokinetics of IDX899 and IDX989, Candidate HIV‐1 Non‐Nucleoside Reverse Transcriptase Inhibitors, Following Oral and Intravenous Administration in Healthy Male Subjects

FemtoMolar measurements using accelerator mass spectrometry

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