Publications

Summary: 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 sensitivityContinue Reading

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Date Posted: 18th October 2011 Summary: 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 haltContinue Reading

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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. Six healthy female subjects of non-childbearing potential were enrolled; each received a single 30 ml oral suspension containing 150 mg of vismodegib with 6.5 ?g of 14C-vismodegib to yield a radioactivity dose of approximately 37 kBq (1000 nCi).
Blood, urine and feces samples were collected over 56 days, to permit sample collection for up to 5 elimination half-lives. Non-radioactive vismodegib was measured in plasma using liquid chromatographic-tandem mass spectrometry (LC-MS/MS) and total radioactivity in plasma, urine and feces was measured using accelerator mass spectrometry. Vismodegib was slowly eliminated by a combination of metabolism and excretion of parent drug, the majority of which was recovered in feces. The estimated excretion of the administered dose was 86.6%, on average with 82.2% and 4.43% recovered in feces and urine, respectively. Vismodegib was predominant in plasma, with concentrations representing greater than 98% of the total circulating drug-related components. Metabolic pathways of vismodegib in human included
oxidation, glucuronidation, and uncommon pyridine ring cleavage. We conclude that
vismodegib and any associated metabolic products are mainly eliminated through feces following oral administration in healthy volunteers.

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Accelerator mass spectromtery (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. This poster describes the progress of an investigation employing a small particle column for faster separation and details the initial results obtained from quantitation of data with reference to a calibration curve which will be compared to the methodology reported previously by Lappin et al (Bioanalysis, Feb 2011, 3 (4), 407-410).

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Abstract: A technique has emerged in the past few years that has enabled a drug’s intravenous pharmacokinetics to be readily obtained in humans without having to conduct extensive toxicology studies by this route of administration or expend protracted efforts in formulation. The technique involves the intravenous administration of a low dose of 14C-labelled drug (termed a tracer dose) concomitantly with a non-labelled extravascular dose given at therapeutic levels. Plasma samples collected over time are analysed to determine the total parent drug concentrations by LC-MS (which essentially measures that arising from the oral dose) and by LC followed by accelerator mass spectrometry (AMS)to determine the 14C-drug concentration (i.e., that arising from the intravenous dose). There are currently no published accounts of how the principles of bioanalytical validation might be applied to intravenous studies using AMS as an analytical technique. The authors describe the primary elements of AMS when used with LC separation and how this off-line technique differs from LC-MS. They then discuss how the principles of bioanalytical validation might be applied to determine selectivity, accuracy, precision and stability of method involving LC followed by AMS analysis.

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