“In the last decade, the administration of reduced doses of 14C-labeled compounds (typically 0.2-1 µCi) combined with AMS has enabled quantitative absorption, metabolism and excretion (AME) studies to be conducted in place of traditional scintillation counting-based studies. The very low doses of radioactivity used in these studies minimize potential safety and regulatory concerns around the use of radioactive material in clinical trials.”
“This study demonstrated that revexepride was rapidly absorbed and exhibited an appreciable level of oral absorption. Almost 100% of total radioactivity was recovered in the urine (mean, 38.2%)and feces (mean, 57.3%) of participants, indicating that these were the major routes of excretion.”
The paper may be accessed here
“Accelerator mass spectrometry was necessary to measure the microtracer quantities of C-14 excreted in the large volumes of dialysate and other biomatrices. An estimated 67 % of the [14C]etelcalcetide dose was recovered in dialysate, urine, and feces 176 days after dose administration. Etelcalcetide was primarily cleared by hemodialysis, with approximately 60 % of the administered dose eliminated in dialysate. Minor excretion was observed in urine and feces.”
“A therapeutic dose was administered that contained a microtracer quantity of [14C]etelcalcetide in order to limit patient exposure to C-14 and to facilitate study conduct in a dialysis clinic. The microtracer approach necessitated using accelerator mass spectrometry (AMS) to achieve the sensitivity required for quantification of the low concentrations of radioactivity excreted in the large volumes of dialysate and other biomatrices over the long study duration.”
“Higher quantities of C-14 more typical for human drug disposition studies were considered but not pursued because of the difficulty in controlling radioactivity contamination if hospitalizations were required during the study. One patient required hospitalization, and microtracer labeling obviated the need for contamination controls. The microtracer approach required the use of AMS for C-14 measurement in biofluids and dialysate. Remarkable detection limits were enabled by AMS, with C-14 concentrations of approximately 0.25 mBq (approximately 6.7 fCi/g) of 14C (approximately 0.06 ng equivalents of etelcalcetide/g) quantified in an approximately 0.35 g dialysate sample prepared from approximately 150 kg of dialysate collected on study day 176.”
The paper may be downloaded from the link here
Due to the low amount of radioactivity anticipated in plasma and in excreta, which were likely to be below the levels that can be reliably measured by liquid scintillation counting (LSC), AMS was also used for plasma, whole blood, urine and feces determinations. Subsequently, metabolic profiles of tozadenant in plasma, urine and feces were determined in pooled samples, using HPLC fractionation followed by AMS analysis in fractions.
The human pharmacokinetics, mass balance and metabolite profiling of tozadenant were successfully characterized.
The only identified species circulating in plasma determined by HPLC+AMS was unchanged tozadenant amounting to approximately 93% of plasma radioactivity in two subjects.
The radiocarbon excretion recovery was approximately 86%, of which 55% fecal and 31% was urinary excretion, respectively. The cumulative excretion of unchanged tozadenent was approximately 30% of the dose (11% in urine and 19% in feces), consistent with the extensive biotransformation of tozadenant through multiple pathways. Fifteen metabolites were identified by their mass fragmentation patterns.
An accepted author version of the paper is available here
Download the publication from here
Retrieve the publication from here
Retrieve the paper from here
Get the paper from Cancer Chemotherapy and Pharmacology here
TAS-102 was approved in America in 2015 as Lonsurf®.
This white paper describes why LC or LC-MS/MS methods must be carefully evaluated as they are adopted for LC+AMS use and why the resultant LC+AMS method must be fully validated before use. A three-batch validation is the only way to ensure method reproducibility and deliver LC+AMS data reliably.
Presented at the 21st Workshop on the Synthesis and Applications of Isotopes and Isotopically Labelled Compounds, International Isotope Society-Central European Division, Bad Soden, Germany
Download the presentation from here
Successful Clinical [14C] Microtracer Investigations – Case Studies from GSK and Genentech
Thursday, 24th September 2015 at 11:00 am EDT – 12:00 pm EDT
Go here to pre-register for the webinar
Shire used 14C + AMS to determine the PK, absorption and excretion of revexepride in a Phase I clinical trial
"...AMS [is] an invaluable tool in our early drug development program, allowing us to quickly assess bioavailability in humans and focus resources on our most promising drug candidates going forward."
Find out how we can help you accelerate your drug-development program.