AstraZeneca – Incorporation of an IV [14C]-microtracer dose into a first in human study to determine the absolute oral bioavailability of AZD5122

May 18, 2016

Retrieve the paper from here


Concomitant Oral And Intravenous Pharmacokinetics Of Dabrafenib, A BRAF Inhibitor, In Patients With BRAF V600 Mutation-positive Solid Tumors

November 28, 2013

Published: J Clin Pharmacol. 2013 Sep;53(9):955-61.
Denton CL, Minthorn E, Carson SW, Young GC, Richards-Peterson LE, Botbyl J, Han C, Morrison RA, Blackman SC, Ouellet D.
Source: GlaxoSmithKline, Research Triangle Park, NC 27709, USA.

Dabrafenib is an orally bioavailable, potent, and selective inhibitor of human wild-type BRAF and CRAF kinases as well as mutant forms of BRAF kinase. The aim of this phase 1, single-center, open-label study in four patients with BRAF mutation-positive solid tumors was to determine the absolute bioavailability of a 150 mg oral dose of dabrafenib. A microtracer study approach, in which a 50 µg radiolabeled intravenous (IV) microdose of dabrafenib was given concomitantly with a 150 mg oral dose, was used to simultaneously recover IV and oral pharmacokinetic parameters. The least squares mean (90% CI) absolute bioavailability of dabrafenib (HPMC capsules) was 94.5% (81.3%, 109.7%). Median T(max) after oral administration was 2.0 hours and the geometric mean terminal half-life was 4.8 hours. The geometric mean clearance and volume of distribution after IV administration were 12.0 L/h and 45.5 L, respectively. Human clearance and volume of distribution at steady state were in agreement with predictions made using allometric scaling of pharmacokinetic parameters from four preclinical species. In conclusion, dabrafenib absolute bioavailability was high, whereas first-pass metabolism was low. Furthermore, the microtracer approach provided an innovative and efficient method for assessing the absolute bioavailability of dabrafenib in patients with advanced cancer.
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Application Of Accelerator Mass Spectrometry In Early Clinical Development

November 25, 2013

This poster was presented in collaboration with Incyte Corp at the 2013 AAPS Annual Meeting held in San Antonio, from 10th – 14th November 2013.

The FDA MIST and subsequent ICH M3 guidelines encourage sponsors to identify major human metabolites at an early stage to demonstrate adequate safety margins in nonclinical studies. However, the human ADME study is often conducted just prior to or in parallel with Phase 3 studies. Authentic standards of metabolites are seldom available early in development and this makes quantitation of metabolites and identification of major metabolites a challenge. Although LC-MS analysis is widely used to support drug metabolism and pharmacokinetics, it is well known that mass spectrometric response is not always quantitative given that the response is dictated by the efficiency of ionization among other factors. This is especially true for metabolites that are cleavage products or conjugates of the parent compound. An alternate strategy was explored in this study. An attempt was made to identify major metabolites of Compound “X” by using a microtrace amount of 14C labeled material co-administered with a pharmacologically relevant dose of ‘cold’ compound during the course of a phase I clinical study. The presence of the microtrace amount of the 14C material allows the use of AMS (Accelerator Mass Spectrometry) to establish a solid quantitative assessment of the major metabolites of the administered compound as a percent of parent compound present, as well as the percent of the total radiolabeled compound present. In addition, the normal dose of cold compound allows qualitative examination of the metabolites formed in human. Performing this assessment early in the clinical development process allows the construction of a coherent, comprehensive development plan early in the process.

If you wish to receive a copy of this poster, please click on the”Download Document” link below or contact Xceleron via email:


Confirmation of the Selectivity of an LC+AMS Assay by Cross-Validation with LC-MS/MS

November 25, 2013

This poster was presented in collaboration with Neurocrine Biosciences Inc at the 2013 AAPS Annual Meeting held in San Antonio, from 10th – 14th November 2013.

Liquid chromatography with Accelerator Mass Spectrometric detection (LC+AMS) is increasingly used as a bioanalytical method. The technique involves chromatographic isolation of the fraction corresponding to the 14C-labeled analyte, which is then analyzed using AMS. The sample processing procedure for AMS involves converting all the carbon in the fraction to graphite. This graphitization process effectively removes potential matrix interferes and minimizes matrix variability, hence the AMS detection technique is not susceptible to the matrix effects due to modulation of ionization that can impact LC-MS assays. Furthermore, because the ultimate analyte is always the same, the technique is independent of the chemical structure of the test compound.

The poster describes a novel approach to the confirmation of the selectivity of the LC+AMS assay, involving cross-validation with an LC-MS/MS method. This approach is applicable where incurred samples are available from a clinical trial in which the 14C-labelled and non-radiolabelled compounds are co-administered by the same dose route and at a dose level sufficient to allow quantification using LC-MS/MS, such as a “traditional” oral dose human AME study.

If you wish to receive a copy of this poster, please click on the”Download Document” link below or contact Xceleron via email:


Confirmation of the Selectivity of an LC+AMS Assay by Cross-Validation with LC-MS/MS

July 23, 2013

Published: 14th Annual Land O’Lakes Bioanalytical Conference, 15-18 July 2013
Authors: Connell Cunningham*, Marie Croft*, Anthony R Hall*, David M Higton*, Mark A Seymour*, Rosa Luo†, Evan Smith†, and Ajay Madan†
*: Xceleron Inc, Germantown, MD; †: Neurocrine Biosciences Inc, San Diego, CA

Objectives: Liquid chromatography with Accelerator Mass Spectrometry detection (LC+AMS) is increasingly used as a bioanalytical technique. It is not susceptible to matrix effects and is independent of chemical structure, because the sample graphitization procedure converts all 14C-containing material in samples into a common analyte, solid carbon. It is, therefore, essential that the analyte is chromatographically resolved from any other 14C-containing species. Although the accuracy and precision of a LC+AMS assay is comparable to liquid chromatography with tandem mass spectrometry (LC-MS/MS), the approach to validation of selectivity does differ. This poster describes a novel approach involving cross-validation with a LC MS/MS method.

Methods: Selected plasma samples from a clinical study whereby healthy human subjects received a single oral dose of [14C]-NBI-X were analyzed by LC+AMS. Aliquots of the same samples were independently analysed using a validated LC MS/MS assay, and results obtained from the two orthogonal methods compared.

Results: Selected samples collected from different subjects after dosing were analysed by both methods. The difference between the results was within ± 15% of the mean for all samples, and there was no apparent temporal trend in the data.

Implications: The differences between the concentrations measured by LC+AMS and LC MS/MS in the same sample were well within the known precision of each assay. Thus, it was concluded that the fraction isolated contained no 14C-labelled species other than [14C]-NBI-X and that the LC+AMS assay was highly selective. This methodology is a valuable tool to unambiguously verify the selectivity of LC+AMS assays during method validation.


A microdose study of 14C-AR-709 in healthy men: pharmacokinetics, absolute bioavailability and concentrations in key compartments of the lung

June 17, 2013

Published: June, 2013, European Journal of Clinical Pharmacology
Authors: G. Lappin (1), M. J. Boyce (2), T. Matzow (2), S. Lociuro (3), M. Seymour (4), S. J. Warrington (2)

In this microdose (phase-0) study,the pharmacokinetics, bioavailability and concentrations in key compartments of the lung, of AR-709, a novel diaminopyrimidine antibiotic for the treatment of respiratory infection, were explored.

Four healthy men each received two single, 100 μg microdoses of 14C-AR-709, 7 days apart: the first was administered intravenously (IV), the second orally. Plasma pharmacokinetics of 14C and unchanged AR-709 were obtained by high-performance liquid chromatography and accelerator mass spectrometry (AMS). Next, 15 healthy men received a single, 100 μg microdose of 14C-AR-709 IV. Plasma, bronchoalveolar lavage fluid, alveolar macrophages and bronchial mucosal biopsy samples were analysed by AMS.

The results of this microdose study indicate that AR-709 attains concentrations appreciably higher within the lung than in plasma. Its low oral bioavailability however, precludes oral administration. Although IV administration would appear to be an effective route of administration, this would limit the use of AR-709 to a clinical setting and would therefore be economically unsustainable. If further clinical development were to be undertaken, therefore, an alternative route of administration would be necessary.

A full copy of this paper can downloaded by following this link.

Author Affiliations:
1. School of Pharmacy, University of Lincoln, Brayford Pool, Lincoln, LN6 7TS, UK
2. Hammersmith Medicines Research, Cumberland Avenue, Park Royal, London, NW10 7EW, United Kingdom
3. Via al Lido—Residenza Fortuna, 6817, Maroggia, Switzerland
4. Xceleron Inc., 20340 Seneca Meadows Parkway, Germantown, MD, 20876, USA


Microdosing studies: a consideration on analytical technology choice

April 10, 2013

Published: 9 April, 2013
Authors: David Higton, Xceleron Inc, Germantown, MD; Jenny Lin, Jim Yamashita, JCL Bioassay USA, Hoffman Estates, IL

Microdosing has been used as an investigative pharmacokinetic tool for approximately 10 years. Initial skepticism of the value of these studies was followed by investigative clinical trials to understand the circumstances when they provide useful data and this has led to routine use. When first introduced, accelerator mass spectrometry coupled with LC fractionation (LC+AMS) was the only technology that could provide the sensitivity required for these studies. Over the years, LC-MS/MS sensitivity has improved so that it is now viable to use this technique for microdosing studies, and a decision needs to be made on what technique to use.

To download a copy of this poster presented at the “7th Workshop on Recent Issues in Bioanalysis” (7th WRIB), please follow the link below.


Microdosed Clinical Investigations are Valid and Cost-Effective

April 4, 2013

Microdose studies are a useful translational and problem-solving tool in drug R&D. They are known to be more predictive of the human in vivo situation than allometric scaling from preclinical species and cost-effectively clarify or replace equivocal preclinical investigations.
Microdose study samples can be analyzed using contemporary LC-MS/MS and LC+AMS platforms. Here we outline the value of a microdose study and how to choose between LC-MS/MS and LC+AMS.


Applications of Accelerator Mass Spectrometry to therapeutic proteins 2: target mediated disposition

September 17, 2012

Poster presented at the 11th International Symposium on the Synthesis and Applications of Isotopes and Isotopically Labelled Compounds (IIS 2012) in Heidelberg, 9-13 September, 2012.It was shown in a previous study that the plasma clearance of T84.66 (anti-carcinoembryonic antigen, CEA) in a xenograft mouse model can be used to test for the presence of CEA as a marker for tumor presence. T84.66 was labeled with 125I and administered in a sufficiently low dose as not to saturate the CEA antigen, to four groups of mice consisting of a control and 3 tumor volumes. Read More »


Applications of Accelerator Mass Spectrometry to therapeutic proteins 1: Protein labeling and distribution studies

September 17, 2012


Poster presented at the 11th International Symposium on the Synthesis and Applications of Isotopes and Isotopically Labelled Compounds (IIS 2012) in Heidelberg, 9-13 September, 2012.Isotopically labeled therapeutic proteins are used in in vivo studies where either sensitive assays are necessary or it is desirable to distinguish a pulse dose of therapeutic protein from endogenous material. Traditionally isotopes of choice are those with the relatively short half-life (eg 125I, t½ 60.25 days) necessary to achieve the high specific activities that drives assay sensitivity. Read More »


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