Lord Dowding Fund for humane research


National Antivisection Society

Microdosing fast forward

15 February 2008


From discovery of a molecule to regulatory approval, the development of a drug takes 10-12 years and now costs around $1.2billion (around £600 million).

New drugs must be evaluated in terms of how they are absorbed, distributed, metabolised and excreted (ADME) by the human body before they can advance towards the market1. Before this point extensive toxicology trials, typically using animals, are carried out.

The fact that as many as 40% of drugs fail to pass phase 1 human trials means that these preclinical studies are failing in predictability[1].

Although industry and regulators are inherently resistant to changes in the established system, the reality is that animal testing is a poor predictor of human reactions and has been estimated to have less than 60% predictive accuracy[2].

Furthermore this approach is not necessary where more relevant tests such as microdosing have the potential to replace animal use in determining suitable pharmacokinetic profiles of compounds[1].

EUMAPP stands for the European Union Microdose AMS Partnership Programme which brings together ten organisations from five countries in recognising the value of microdosing in drug development. The 30-month programme, lead by the strategic consultancy Xceleron and funded by the EU to a value of over €3million, aims to demonstrate microdosing as reliable and accurate, and in conjunction with in silico models aims to predict the human metabolism of drugs using data derived from microdosing[3].

The steering committee of EUMAPP comprises an authorised representative from each participating organisation[4].

EUMAPP will also look to verify human microdosing as a drug development approach, convincing the pharmaceutical industry of its merits and adding another seven drugs to the portfolio of compounds tested by Xceleron. The project is evidence that the value of microdosing has been recognised, and gives Europe a chance to lead the field[3].

A ‘microdose’ is defined as less than one hundredth of the proposed pharmacological dose but never exceeding 100µg[5]. Drug levels from microdosing can be measured in any biological sample such as plasma or urine to determine ADME and pharmacokinetic characteristics of a drug6.
This analysis is carried out using an Accelerator Mass Spectrometer (AMS). This is the most sensitive analytical tool available and is used to study the samples from humans, allowing early metabolism data to be obtained before going into human phase 1 trials[7].

AMS is able to directly count individual atoms and is so sensitive it has the ability to detect a liquid compound even after one litre of it has been diluted in the world’s oceans[1].

By conducting Human Phase 0 microdosing, drug candidates can be efficiently tested, directly in the relevant species, using trace doses to obtain early pharmacokinetic information.
This ultra sensitive analytical-technique allows greater predictability than animal studies and reduces the pre-clinical testing time from 18 months to 6 months. It also permits enhanced drug candidate selection and results in safer clinical trials[3].

The drug candidates selected for testing in the EUMAPP project were agreed upon because they were representative examples of drugs that exhibit properties in humans that are difficult to predict in animal or in vitro models. They were also chosen as drugs with properties that might be difficult to predict at a therapeutic dose from microdose data[8].

The preclinical animal tests which the pharmaceutical industry carries out are long, costly and unreliable. The reduced time that microdosing and AMS take to assess drugs in development will mean a reduction in the cost of producing drugs. This in turn could mean that more candidate drugs can be tested before clinical trials and potentially more drugs making it onto the market, leading to improved human health.

(1) Rowland, M (2006) Microdosing and the 3Rs, NC3Rs #5
(2) Ward, K. W and Smith, B. R (2004) A comprehensive quantitative and qualitative evalustion of extrapolation of intravenous pharmacokinetic parameters from rat, dog and monkey to humans. I. clearance, Drug metabolism and disposition, 32 (6): 603-611
(3) http://www.xceleron.com/metadot/index.pl?id=2572&isa=DBRow&op=show
(4) http://www.eumapp.com/index.php?content=committees
(5) http://www.emea.europa.eu/pdfs/human/swp/259902en.pdf
(6) http://www.xceleron.com/metadot/index.pl?iid=2494
(7) http://www.xceleron.com/metadot/index.pl?id=2502&isa=Category&op=show
(8) Lappin, G (2007) Translational medicine microdosing workshop: A General Introduction to Microdosing. http://www.xceleron.com/metadot/index.pl?id=2710&isa=Category&op=show

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