Analytical Validation of Accelerator Mass Spectrometry for Pharmaceutical Development

Keck, B.; Ognibene, Ted; Vogel, John S.

doi:10.4155/bio.10.14

Cited by 34 publications

(23 citation statements)

References 36 publications

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“…CO 2 was released by heating of the trap and transferred to a vacuum syringe using helium. The resulting 6% v/v gas mixture of CO 2 with helium was infused at a pressure of 1 bar at 60 μL/min into the titanium target in the SO110 ion source of a 1 MV Tandetron AMS (High Voltage Engineering Europe B.V., The Netherlands) . As the AMS solely counts [ 14 C] atoms, the analysis is universal.…”

Section: Methodsmentioning

confidence: 99%

Microdosing of a Carbon‐14 Labeled Protein in Healthy Volunteers Accurately Predicts Its Pharmacokinetics at Therapeutic Dosages

Vlaming¹,

Duijn²,

Dillingh

et al. 2015

Clin Pharma and Therapeutics

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Preclinical development of new biological entities (NBEs), such as human protein therapeutics, requires considerable expenditure of time and costs. Poor prediction of pharmacokinetics in humans further reduces net efficiency. In this study, we show for the first time that pharmacokinetic data of NBEs in humans can be successfully obtained early in the drug development process by the use of microdosing in a small group of healthy subjects combined with ultrasensitive accelerator mass spectrometry (AMS). After only minimal preclinical testing, we performed a first-in-human phase 0/phase 1 trial with a human recombinant therapeutic protein (RESCuing Alkaline Phosphatase, human recombinant placental alkaline phosphatase [hRESCAP]) to assess its safety and kinetics. Pharmacokinetic analysis showed dose linearity from microdose (53 μg) [(14) C]-hRESCAP to therapeutic doses (up to 5.3 mg) of the protein in healthy volunteers. This study demonstrates the value of a microdosing approach in a very small cohort for accelerating the clinical development of NBEs.

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Section: Methodsmentioning

confidence: 99%

Microdosing of a Carbon‐14 Labeled Protein in Healthy Volunteers Accurately Predicts Its Pharmacokinetics at Therapeutic Dosages

Vlaming¹,

Duijn²,

Dillingh

et al. 2015

Clin Pharma and Therapeutics

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“…In practice, AMS provides the linear response necessary for this approach. 30,33,35 The data presented in Figure 1 demonstrate that the AMS response is linear up to 0 dpm/mL. The derived LLOQ Z=0 in this study is 0.00363 dpm/mL for plasma 14 C-SCH 900518 analysis on the basis of the experimental S c , S s , and U c calculated using eq 4.…”

Section: Precision and Accuracy In Ams Analysis Of Biologicalmentioning

confidence: 96%

Precision and Accuracy in the Quantitative Analysis of Biological Samples by Accelerator Mass Spectrometry: Application in Microdose Absolute Bioavailability Studies

Gao¹,

Li²,

Kasserra³

et al. 2011

Anal. Chem.

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Determination of the pharmacokinetics and absolute bioavailability of an experimental compound, SCH 900518, following a 89.7 nCi (100 μg) intravenous (iv) dose of 14C-SCH 900518 2 h post 200 mg oral administration of nonradiolabeled SCH 900518 to six healthy male subjects has been described. The plasma concentration of SCH 900518 was measured using a validated LC–MS/MS system, and accelerator mass spectrometry (AMS) was used for quantitative plasma 14C-SCH 900518 concentration determination. Calibration standards and quality controls were included for every batch of sample analysis by AMS to ensure acceptable quality of the assay. Plasma 14C-SCH 900518 concentrations were derived from the regression function established from the calibration standards, rather than directly from isotopic ratios from AMS measurement. The precision and accuracy of quality controls and calibration standards met the requirements of bioanalytical guidance (U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Center for Veterinary Medicine. Guidance for Industry: Bioanalytical Method Validation (ucm070107), May 2001. ). The AMS measurement had a linear response range from 0.0159 to 9.07 dpm/mL for plasma 14C-SCH 900158 concentrations. The CV and accuracy were 3.4–8.5% and 94–108% (82–119% for the lower limit of quantitation (LLOQ)), respectively, with a correlation coefficient of 0.9998. The absolute bioavailability was calculated from the dose-normalized area under the curve of iv and oral doses after the plasma concentrations were plotted vs the sampling time post oral dose. The mean absolute bioavailability of SCH 900518 was 40.8% (range 16.8–60.6%). The typical accuracy and standard deviation in AMS quantitative analysis of drugs from human plasma samples have been reported for the first time, and the impact of these parameters on quantitative analysis was further assessed using the Z factor. The use of the lowest achievable LLOQ Z =0 derived from statistical analysis of the control and low-concentration standards for AMS measurements is proposed in future studies.

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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%

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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Analytical Validation of Accelerator Mass Spectrometry for Pharmaceutical Development

Cited by 34 publications

References 36 publications

Microdosing of a Carbon‐14 Labeled Protein in Healthy Volunteers Accurately Predicts Its Pharmacokinetics at Therapeutic Dosages

Microdosing of a Carbon‐14 Labeled Protein in Healthy Volunteers Accurately Predicts Its Pharmacokinetics at Therapeutic Dosages

Precision and Accuracy in the Quantitative Analysis of Biological Samples by Accelerator Mass Spectrometry: Application in Microdose Absolute Bioavailability Studies

Bioanalytical Aspects of Clinical Mass Balance Studies in Oncology

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