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.
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.
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 »
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 »
Accelerator mass spectrometry (AMS), in conjunction with LC, has been applied as a quantitative tool which enables innovative study designs employing 14C enriched analytes. The use of the 14C-label permits the determination of absolute bioavailability, clearance and volume of distribution by IV administration of the 14C analyte concomitant with extravascular pharmacological dose of unlabelled compound. Read More »
Unilever R&D, Vlaardingen, The Netherlands (G.D.); Unilever Safety & Environmental Assurance Centre, Colworth, United Kingdom (B.C., S.W.); Xceleron Ltd., York, United Kingdom (J.H., D.S., G.L.); and Medical University of Vienna, Vienna, Austria (A.B., M.M., M.Z.)
The metabolic turnover, absolute oral bioavailability, clearance, and volume of distribution for Beta-sitosterol were measured in healthy subjects. [14C]Beta-Sitosterol was used as an isotopic tracer to distinguish pulse doses from dietary sources and was administered by both oral and intravenous routes. Read More »
The metabolites in safety testing and ICH-M3 guidance documents emphasize the importance of metabolites when considering safety aspects for new drugs. Both guidances state that relevant metabolites should have safety coverage in humans (although the guidelines have different definitions of relevant metabolites). Read More »
This poster, published at the ASCPT meeting in Dallas, Texas, in 2011, describes how scientists at Genentech used the AMS enabled IV tracer approach to investigate the previously observed non-linear pharmacokinetics (PK) of vismodegib (GDC-0449).
By administering a 14C-labelled IV microtracer of Vismodigib in addition to an oral dose, they were able to determine how PK behavior changed with multiple daily dosing relative to a single dose.
A paper on a presentation by Dr Mark Seymour on the use of AMS as a frontline technique in bioanalytical detection has been published in the December 2011 issue of Bioanalysis. Read More »
Target Mediated Disposition of 14C-anti-CEA using Accelerator Mass SpectrometryIt has been shown in a previous study using Iodine-125, that the plasma clearance of T84.66 (anticarcinoembryonic antigen, CEA) in a xenograft mouse model can be used to test for the presence of CEA-positive tumors. Transferring the technique into humans would be problematic because of the low doses of antibody required and the potential radioactive burden required to achieve sufficient assay sensitivity. Read More »
Microdosing studies: a consideration on analytical technology choice
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