BioWorld International Correspondent

LONDON - A UK company has developed measuring technology that makes it possible to bypass swathes of toxicology and animal studies and assess the pharmacokinetic and ADME characteristics of candidate drugs in human volunteers.

It calls the process Phase 0 trials.

Xceleron Ltd. says there is European and FDA acceptance for the technique, which involves administering radiolabeled drugs in such small amounts - called microdoses - that they are not pharmacologically active. Blood and urine samples are subsequently assessed using the company's Accelerator Mass Spectrometer (AMS), which Xceleron claims is the most sensitive measuring device ever invented and says it can count individual atoms.

ADME stands for absorption, distribution, metabolism and excretion.

To date, there have been only a handful of Phase 0 studies, but Xceleron, based in York, UK, now has brought together certain undisclosed companies to form CREAM (Consortium for Resourcing and Evaluating AMS Microdosing) to fund human trials and validate the technology.

Jeremy Hague, Xceleron's European business development manager, told BioWorld International, "The aim of the program is to demonstrate that what happens at the microdose level can be predictive of the effects of a pharmacological dose." The trials to date, working with approved drugs, indicate that is the case.

Six compounds have been chosen for the trials, five of which are marketed drugs. "We have deliberately chosen drugs that had a difficult time in development," Hague said. "For example, they had wonderful bioavailability in dogs and rats and very poor bioavailability in humans, so the companies had to go back and reformulate."

Xceleron says being able to analyze the activity of such minute amounts of candidate drugs will cut a significant amount of time and waste from the drug development cycle. Some toxicity testing is required, but human microdosing studies can be performed within four months of new candidate selection. It will be possible to rank candidates on the basis of ADME characteristics in advance of full toxicology and animal studies, and cut down on the 30 percent failure rate in Phase I work, Xceleron said.

"Most drugs fail because of PK and ADME issues, when you have already killed a lot of animals and exposed humans to therapeutic doses of potentially harmful substances," Hague said. "Now you can figure out much earlier on, which candidates will pass Phase I."

Xceleron announced this week that it is linking with a clinical research organization, Pharmaceutical Profiles Ltd. of Nottingham, to provide a one-stop Phase 0 clinical trial service.

A microdose is defined as less than 1 percent of the dose calculated to have a pharmacological effect, based on preliminary in vivo and in vitro toxicology. Only a single dose may be administered, and the maximum dose is 100 micrograms. Only 20 grams of drug are needed to carry out Phase 0 trials, compared to kilogram quantities required for Phase I.

The European Agency for the Evaluation of Medicinal Products gave the go-ahead for microdose trials in July. The trials must be approved by ethics committees, but do not need full Phase I approval. Hague said the FDA has indicated to Xceleron that Phase 0 microdose trials come under existing rules on radiopharmaceuticals, and the company is seeking formal confirmation of that position. There has been no formal approval for the microdosing technique.

Earlier this year the UK Animal Procedures Committee, which advises the UK government, advocated the use of microdosing as a way to cut down on animal testing.

Xceleron was formed in February around a company that was spun out of York University in 1997, and the university is still the major shareholder. The company provides other measuring services to pharmaceutical companies and became profitable this year.

There are around 60 AMS machines worldwide, mainly used for carbon dating. Hague said the power of Xceleron's machine derives from the fact that it has been fine tuned for biomedical applications.