Services

The AMS facility

14C is the most common radioisotope used for hADME studies. A total radioactivity method is qualified for human plasma, urine, whole blood, feces and exhaled air. Analysis can also be performed on CSF, bile and tissues. Samples are introduced via an automated sample combustion device that generates CO2, which is directed to the AMS via an interface. The speed of the analysis (a single sample is completed in less than 10 minutes), supports discharge studies from a clinical site.

For metabolite profiling purposes the UPLC is coupled in line to a high resolution mass spectrometer and fraction collector. The individual fractions collected are quantified for 14C levels to generate a radio-chromatogram and data on the abundance of parent and metabolites present in a specific matrix sample is easily generated. As continuously accurate mass spectra and fragmentation spectra are acquired during the chromatographic run these can be used for the compound identification. From a single injection both datasets are acquired and therefore 100% aligned.

Our facility is science and quality driven and operates under GLP standards.

What services do we offer?

Microtracing (possible from Phase I)

New drugs in development are commonly administered to humans for the first time in Phase I trials, to obtain primary data on pharmacokinetics. By including a microtracer in the study additional valuable data can be generated from the same cohort of volunteers. By administration of the microtrace via the same route as the “normal” dose excretion route, mass balance and metabolite profiling data can be obtained. Absolute bioavailability data on the other hand requires dosing of the microtrace via the other route (iv versus oral or reversed). In the end a more complete dataset is available to better map the drug disposition for the new compound of interest.

  • Absolute bioavailability data
  • A PK profile (for parent drug and known metabolites)
  • A metabolite profile including metabolite identification
  • Mass balance data
  • Routes of excretion
  • Information on the first pass effect
  • Information on the fraction absorbed
  • Information on clearance
  • Information on volume of distribution
  • Estimation of fraction absorbed
  • Add on to any existing clinical trial
  • Peregrion supports discharge studies from a clinical unit (when located in the Netherlands)
  • Qualified 14C-labeled material may be used instead of 14C-labeled material produced under full GMP
  • Very low sample volumes are required (i.e. 5 uL of plasma for a total radioactivity analysis and 50 uL of plasma for the generation of PK data or metabolite profling data)
  • Can be applied both to small molecules and biologicals

Microdosing (Phase 0)

Very early in drug development in Phase 0, microdosing can be used to investigate for example the pharmacokinetics, absorption and excretion of a drug candidate. As the microdose itself (e.g. 100 µg) is of no toxicological concern, only a limited pre-clinical package is required to conduct such a study. This comes with the advantage that fewer lab animals are needed. The generation of actual human data is valuable to for decision making, for example candidate selection or the optimization of the phase I trials design. Multiple drugs can be administered simultaneously, which is called cassette microdosing. A typical microdosing study consists of approximately 6 volunteers per study. The microdose can be administered via any route, e.g. oral or intraveneous.

  • A PK profile (for parent drug and known metabolites)
  • A metabolite profile (no identification)
  • Mass balance data
  • Dose linearity from microdose to therapeutic dose can be predicted
  • Very low sample volumes (i.e. 5 uL of plasma for a total radioactivity analysis and 50 uL of plasma for the generation of PK data or metabolite profling data)
  • Only a limited preclinical package is required
  • Extended 14 day single dose, one species (rodent), intended route or i.v.
  • Genotoxicity testing not advised
  • SAR
  • Genotoxicity
  • No QWBA at this stage
  • To Apply Microdosing or Not? Recommendations to Single Out Compounds with Non-Linear Pharmacokinetics. Clinical Pharmacokinetics 2015. DOI 10.1007/s40262-015-0308-9