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 »
A Resource and Data Quality Comparison: Absolute Bioavailability Data from an Oral / IV Crossover and an IV Isotropic Tracer Clinical Design. This poster, presented by AstraZeneca and Xceleron at the meeting of the American Association of Pharmaceutical Scientists (AAPS) in Washington DC in October 2011, describes the us of an IV microtracer study design to obtain information on absolute bioavailability and IV pharmacokinetics. Read More »
Probing Intrinsic Pathways: a Novel Approach to the Measurement of Metabolic Turnover. Studying compounds with high natural occurrence or dietary background in humans is problematic because the dose of metabolite or precursor must be very small to avoid perturbing naturally-occurring pools, intravenous administration is required to obtain clearance and metabolic-turn-over data, and extreme sensitivity is required. Read More »
In this month’s Xenobiotica, scientists from Pfizer, in collaboration with Xceleron, describe a study in which AMS enabled microdosing was used to compare the oral and IV pharmacokinetics of preclinical development drug candidate, PF-4776548.This provided a relatively low cost, clear decision making approach,resulting in the decision to halt further development of PF-4776548, saving money and resources.
Vismodegib (GDC-0449), a small molecule Hedgehog Pathway Inhibitor, was well tolerated in patients with solid tumors and showed promising efficacy in advanced basal cell carcinoma in a Phase I trial. The purpose of the present study was to determine routes of elimination and extent of vismodegib metabolism, including assessment and identification of metabolites in plasma, urine and feces.
Pharmaron Acquires Majority Stake in SNBL CPC
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