New data adds weight to case for microdosing

By Kirsty Barnes

- Last updated on GMT

Related tags: Pharmacology

Newly-released data appears to add weight to the case for
microdosing as a means to more accurately predict pharmacological
dose absorption, metabolism, distribution and elimination (ADME)
and pharmacokinetic (PK) outcomes in drug development.

Preliminary results from the 30-month, €2m European Union Microdose AMS Partnership Programme (EUMAPP) "strongly endorse the ability of microdosing to provide valuable human data at the earliest stages of exploratory clinical development​", said Dr Colin Garner, president and CEO of microdosing services firm Xceleron and chair of the EUMAPP steering committee. He did concede that "the outputs of the programme still need to undergo rigorous scrutiny and detailed interpretation​". However, the results are strengthened by the fact that the compounds selected for the project were done so in order to "rigorously test" the predictability of human microdosing by studying drugs that exhibited properties in humans that are difficult to predict in animal or in vitro​ models, and drugs with properties that, it was suspected, might be difficult to predict at a therapeutic dose from microdose data, he said. The concept of microdosing - otherwise known as a Phase 0 study - is that it is conducted as an interim step between preclinical and Phase I studies, where a small number (up to seven) of human volunteers take doses of experimental new drugs that are just 1/100 of therapeutic dose so there is no risk of toxicity, in order to obtain early useful PK information. The technique uses accelerator mass spectroscopy (AMS) to count radioactive carbon atoms (14C) in blood, urine and or faecal samples from volunteers who have taken radiolabelled doses of test compounds. Supporters of microdosing studies claim they can identify compounds likely to fail earlier, preventing wasted investment of time and resources, as a proportion of these failures can be attributed to poor PK data leading to potential efficacy or safety issues in humans, and it is these weaknesses that microdosing is designed to pick up. However, being a new concept, the pharma industry has remained largely sceptical until more research has been done. "We are dealing with a very conservative industry and this scepticism will last until we have more data​," Garner told Outsourcing-Pharma.com in an earlier interview. "We could debate this back and forth but the only solution is to conduct more studies​." As such, EUMAPP is being coordinated by Xceleron, who first pioneered the concept of microdosing, and funded by the European Commission and gathers together 10 organisations from the UK, Sweden, The Netherlands, France and Poland with the aim of evaluating microdosing for drug development and arriving at recommendations as to how and when it should be used. In addition the consortium aims to certify the high and low voltage AMS technique as the most accurate, reproducible and appropriate of analytical methodologies for all measurements required by microdosing studies. Commenting on the preliminary results, Professor Malcolm Rowland, scientific advisor to the EUMAPP consortium, said: "Generally the EUMAPP results are sufficiently encouraging to continue to support the view that, applied intelligently, microdosing coupled with AMS, offers an additional tool to facilitate earlier than otherwise possible decisions in candidate selection​". Dr Roeline Jochemsen, director of Clinical Pharmacokinetics & Pharmacometrics at Institut de Recherches Internationales Servier went a step further, stating that: "The EUMAPP study provides increased confidence in the predictivity of microdosing​". Meanwhile, pushing ahead with its penchant for microdosing, Xceleron announced that it has now developed a database of 25 compounds with data on both microdose and pharmacological dose that show 80 per cent predictability of PK parameters over dose ranges of a hundred-fold and more (in some cases many thousand-fold) for a "diverse range of compounds​".

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