The successful application of carbon isotopes in preclinical and clinical pharmaceutical research


Presented:  21st Workshop on the Synthesis and Applications of Isotopes and Isotopically Labelled Compounds, International Isotope Society-Central European Division, Bad Soden, Germany

By:  Mr. Stephen English

Source:  Xceleron, Inc., 20340 Seneca Meadows Parkway, Germantown, MD 20876, Friday, 2nd October 2015

Abstract

The application of carbon isotopes (14C) and Accelerator Mass Spectrometry (AMS) in pharmaceutical clinical research has yielded significant savings in time and expense when compared with conventional isotope uses and analytical platforms.  Much of these savings can be attributed to the unique advantages conferred by isotopes as microtracers and analytical sensitivity in therapeutic-level drug investigations.  Growth in adoption of new isotope applications is predicated on use of robust analytical methodology.  Stephen presented Xceleron’s experience in developing robust qualitative and quantitative analytical methodology to support clinical mass balance, metabolite profile and critical pharmacokinetic parameters.

Stephen also described how the combination of 14C + AMS is proving invaluable in preclinical drug research and development.  He discussed the measurement of protein drug target kinetics, antibody-drug conjugate disposition and peptide metabolism as examples.

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Approaches to Intravenous Clinical Pharmacokinetics: Recent Developments with Isotopic Microtracers


Published:  J Clin Pharmacol.  2015 Sep; XX (XX) 1-13

Lappin, G

Obtaining pharmacokinetic data from the intravenous route for drugs intended for oral administration has traditionally been expensive and time consuming because of the toxicology requirements and challenges in intravenous formulations. Such studies are necessary, however, particularly when regulatory agencies request absolute bioavailability data. A method has emerged whereby the drug administered intravenously is isotopically labeled and dosed at a maximum of 100 µg concomitantly with an oral administration given at a therapeutically relevant level. The intravenous administration has been termed a microtracer and obviates intravenous toxicology requirements as well as simplifying formulations. The study design also essentially removes issues of nonlinear pharmacokinetics that may occur when oral and intravenous doses are administered separately. This review examines the methodology and the literature to date, including those studies intended for regulatory submission. The method has been extended to the study of prodrug–to–active drug kinetics and to obtaining clearance, volume of distribution, and absolute bioavailability at steady-state conditions.

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If you would like more information on how Xceleron can help you with your innovative Phase I clinical study designs, please do not hesitate to email info@xceleron.com

 

Surveying the Boundaries of Accelerator Mass Spectrometry: The Widening Scope of an Evolving Technology


Presented:  12th International Symposium on the Synthesis and Applications of Isotopes and Isotopically Labelled Compounds, Princeton NJ, 2015
By:  Dr. Stephen English
Source:  Xceleron, Inc., 20340 Seneca Meadows Parkway, Germantown, MD 20876

Abstract

Accelerator mass spectrometry (AMS) has been used for quantitative analysis of analytes labeled with 14C in a range of biological matrices since the early 1990s. Applications of the technique have progressed from total 14C analysis to determine mass balance to specific analyte quantitation in microtracer studies, using LC fractionation with off-line analysis of the fractions (i.e. bioanalysis by LC+AMS).  Most recently, the full robustness of AMS as an analytical technique has become more obvious as a compliment to a variety of preclinical and clinical approaches and investigational protocols.

In this presentation Dr. English will address four topics:

  • The means by which Xceleron has overcome the analytical challenges at very low concentrations caused by a range of biological matrices, non-specific binding and poor extraction efficiency
  • Detailed Quality Control results of 20 quantitative microtracer assays utilizing full calibration curves and 3-batch validation procedures
  • A recent case study in which AMS was used to determine drug Mass Balance and Metabolism in patients with impaired metabolic states over 170 days and from atypical biological matrices
  • Recent research into simultaneous detection of all carbon isotopes by AMS

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Mass Balance Study of TAS-102 Using 14C Labeling Analyzed by Accelerator Mass Spectrometry


TAS-102 is a 2:1 ratio oral formulation of trifluridine (FTD) and tipiracil hydrochloride (TPI). Although the metabolism of FTD has been reported, the metabolic fate and excretion of TAS-102 is unknown.

Patients with advanced solid tumors (6 M/2 F; median age 58 years; PS 0-1) enrolled. Group A (N = 4) received 60 mg TAS-102 with 200 nCi [14C]-FTD, and group B (N = 4) received 60 mg TAS-102 with 1000 nCi [14C]-TPI orally. Plasma, blood, urine, feces, and expired air (group A only) were collected up to 168 h, and were analyzed for 14C by accelerator mass spectrometry and for components of TAS-102 by LC-MS/MS.

FTD: Approximately 12% of plasma 14C AUC is accounted for by FTD (7%) and FTY (5%). The long half-life of 14C in plasma (>300 h) is in line with the moderate recovery of FTD-related 14C in the excreta over the 168 h collection period. 14C was mostly excreted in urine, and only very little was in feces and expired air, suggesting good absorption and limited metabolism of the pyrimidine ring. TPI: Approximately 34% of plasma 14C AUC is accounted for by TPI. 14C was mostly excreted in feces likely due to poor absorption of TPI. The majority of absorbed 14C was excreted into urine.

The mass balance of FTD and TPI as part of TAS-102 was successful. The majority of the 14C-TPI dose was recovered in feces. Approximately 60% of the 14C-FTD dose was recovered, largely in urine. The current data support the rationale of hepatic and renal dysfunction studies of TAS-102.

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Tiered validation of LC + AMS assays: Recommendations for best practices


Presented: European Bioanalysis Open Forum, Barcelona, 2014.
By; English, S.; Croft, M.; Pankratz, T.; Seymour, M.
Source: Xceleron, 20340 Seneca Meadows Parkway, Germantown, MD 20876

Abstract

Xceleron scientists have been active in the discussion of tiered validation options for LC + AMS.  In this presentation, the authors approach the subject in the context of;

  • LC + AMS vs LC-MS/MS (similarities and differences)
  • The construction of an LC + AMS assay
  • A full validation for LC +AMS
  • Selectivity and matrix effects.

Assay performance is discussed using three-batch inter-day data on calibration standard accuracy, QC accuracy and QC precision for 14 compounds.  The authors also address the usefulness of an internal standard and conclude that the approach is useful to understand assay performance when using complex methods such as 2D chiral chromatography.

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What’s the Best Way to Measure Absolute Bioavailaility?


Presented: Land o’ Lakes, 2014
English, S.; Croft, M.; Lin, J.; Pankratz, T.; Seymour, M.; Yamashita, J.
Source: Xceleron, 20340 Seneca Meadows Parkway, Germantown, MD 20876

Abstract
Traditionally, absolute bioavailability has been determined using a crossover clinical design, requiring administration of an IV dose expected to give plasma concentrations similar to those arising from the therapeutic extravascular dose.

An alternative, scientifically superior and more resource-efficient approach is to administer an isotopically-labelled IV microtracer dose concomitantly with the EV dose.  A growing number of such studies are now being conducted.

The concomittant dosing approach can be implemented using either a stable isotope (13C) or a radioactive isotope (14C).  The utility of the methodology is underpinned by the availability of robust analytical methods, with sufficient sensitivity to detect the very low concentrations of labelled compound arising from the IV dose, for both isotopes.  The choice is largely dependent on the physicochemical and pharmacokinetic characteristics of the compound.  Here we assess the relative merits of using LC-MS/MS and a 13C-labelled tracer or using LC+AMS and 14C and present a decision tree as an aid to making the decision.
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Utilization of AMS and HRMS for Metabolite Profiling and Identification of 14C Revexepride (SSP-002358) in a Human Microtracer Phase I Study


Presented: ASMS, 2014
Bobba, S., Ding, J., Chowdhury, G., Cardinal, K., Press, R. J., Oelke, C., Pankratz, T., Croft, M., Scarfe, G.
Source: Xceleron, 20340 Seneca Meadows Parkway, Germantown, MD 20876

Abstract

Revexepride (a 5-HT4 receptor agonist) is among the first of a new class of selective prokinetic agents shown to accelerate gastricemptying and stimulate gastrointestinal motility. Although preliminary results of animal/preclinical absorption, metabolism and excretion (AME) data are available, the elimination pathways of revexepride in humans are largely unknown. Thus, one of the main purposes of this open-label, non-randomized Phase I study was to explore the AME profile of [14C]revexepride in healthy male study participants.

Based on the quantitative whole-body autoradiography (QWBA) data after oral administration of [14C]revexepride to rats, the estimated radioactivity of [14C]revexepride would be approximately 1.8 x 109 Sv/Bq (with 80% of this going to the eye), which would exceed the maximum exposure limits allowed by the FDA (21 CFR 361.1) by about 7 times. As the radiochemical analysis using the traditional measurement method of liquid scintillation counting would be sensitive method needed to be employed in this study, i.e., accelerator mass spectrometry (AMS).

The sensitivity of AMS permits the use of a much lower level of radioactivity such that the dose of radioactivity given in this study was approximately 200nCi. In this study, AMS was used for radioanalysis and metabolite profiling to obtain detailed quantitative information on the circulating metabolites, the extent of metabolism, and routes and rates of excretion for revexepride and its metabolites, while high-resolution accurate mass (HRAM) mass spectrometry was used for metabolite identification.
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To What Extent Has Microdosing Been Adopted by the Pharmaceutical Industry

Presentation Date: 18th October 2012

This is a presentation by Xceleron CSO, Dr Graham Lappin, on the adoption of microdosing by the pharmaceutical industry and was given at the 2012 Annual AAPS Meeting in Chicago from 14-18 October at McCormick Place, Chicago. The presentation was part of a Thursday Morning Symposium on “Microdosing: Past Experience and Future Role in Translational Medicine” moderated by Malcolm Rowland of the University of Manchester. Read More »

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Microdosing: Past and Future


This is a presentation given by Xceleron CSO, Dr Graham Lappin, at the DIA’s annual meeting, held June 24-28, 2012, in Philadelphia, PA. Read More »

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Analytical Technologies for Metabolite Identification and Quantitation

Presentation Date: 17th March, 2012

Copy of presentation given by Xceleron’s CSO, Dr Graham Lappin, at the 2012 ASCPT meeting, held at the Gaylord National Hotel & Convention Center, National Harbor, Maryland from 12 – 17th March

Presenters / Speakers

This talk was given as part of a workshop called “Metabolites in Safety Testing: What Have Clinical Pharmacologists MIST” on the morning of Saturday 17th March and which included speakers from the FDA and Pfizer.
The presentation gives an overview on the methods available for the identification and quantitation of metabolites to satisfy the MIST guidance, as well as describing how Accelerator Mass Spectrometry can be used as part of an overall strategy in combination with other technologies to give quantifiable measurement of metabolites in all matrices. Case studies from industry are also given as examples.

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