| Human volunteers taking doses of experimental new drugs that
are just one hundreth of those calculated to give a pharmacological effect
could
soon save pharmaceutical companies millions of pounds in wasted research.
By outlining the kind of
abbreviated preclinical toxicology and mutagenicity studies that will
be needed before these so-called microdosing studies can be carried out,
both European and US drug regulators have now given their seal of approval
to what have been christened “phase 0 clinical trials”. As
a result, a growing number
of pharmaceutical companies are taking an interest in this new technique,
which borrows high sensitivity carbon dating technology from archaeologists,
to reduce dramatically the dose of a drug that is required to get key
pharmacokinetic and bioavailability data.
Ian Wilding, special professor, School of Pharmacy, University of Nottingham,
and co-founder and scientific adviser to research company Pharmaceutical
Profiles, predicts that human microdosing could help to address the current
crisis in drug development of rising costs and falling numbers of blockbuster
drugs. “Seventy-five per cent of the $900m it now costs to get
a new drug to the market can be attributed to earlier failures, and 40
per cent of drugs that fail in phase
I clinical trials do so because of inapprop-riate pharmacokinetics,” Professor
Wilding explained to The Journal. He added that getting drugs into humans
at an earlier — phase 0 — stage might not necessarily increase
the hit rate of pharmaceutical research and development but it will help
companies to “fail early, fail fast and fail cheaply”.
Colin Garner, chief executive officer of Xceleron, York-based specialists
in the carbon dating technology required for microdosing, calculates
that the technique will provide key pharmacokinetic data for a new compound
in four to six months, at a cost of about $0.35m per molecule. This compares
with 12–18 months and a $3–5m price tag for taking a compound
through current phase I studies. “People always hope that their
molecule will make it and there is great reluctance to kill it. But we
have to be hard and dispassionate, and ensure that molecules that fail,
fail early,” Professor Garner said.
Microdosing reduces costs because the
microgram amounts of compounds that are required do not need to be expensively
scaled up to manufacturing standards of production. Fewer animal studies
are needed to support microdosing than phase I studies so there are ethical
as well as cost advantages. And the
information from microdosing studies can feed into better design of subsequent
dose ranging and other phase I trials.
The microdosing technique in which there is currently most interest uses
accelerator mass spectroscopy (AMS) to count radioactive carbon atoms
(usually 14C) in blood, urine and or faecal samples from volunteers who
have taken radiolabelled doses of test compounds. The tiny amounts of
radiation that are needed and the hypersensitivity of the technology
are mind-boggling. Professor Garner explained that the dose of radioactivity
used for AMS studies falls below the 1mSv level which requires approval
by the Administration of Radioactive Substances Advisory Committee (ARSAC).
He likens it to the radiation dose to which an individual would be exposed
during a 10-minute walk in the street.
The level of radioactivity needed for
microdosing is so small because AMS can measure 14C levels in human samples
in
attograms (10–18g) and zeptograms (10–21g). Weeks after a
volunteer is dosed with a 14C-labelled compound, AMS can detect levels
of the parent drug and its metabolites in blood or other samples, making
it an ideal tool for testing the pharmacokinetics of drugs with long
half-lives or poor bioavailability.
New possibilities
Professor Garner predicts that with such small amounts of drug being
administered microdosing opens up the possibility of including women
of child-bearing age in pharmacokinetic studies as well as patients
with diseases likely to affect drug metabolism — not just healthy
volunteers. However, the big question hanging over microdosing, has
been how well the pharmacokinetic data that are collected correlate
with data gathered from conventional phase I studies using pharmacological
doses of drugs. To this end, the consortium for resourcing and evaluating
AMS microdosing (CREAM) trial was set up to show whether microdosing
could predict the pharmacokinetic properties at therapeutic doses of
five drugs with different properties. These were warfarin, ZK 253 (an
anti-oestrogen
compound), diazepam, midazolam and erythromycin.
Presenting the results at a conference in London in June, Malcolm Rowland,
research professor of pharmacy, Centre for Applied Pharmacokinetics Research,
University of Manchester, explained that each drug was chosen to address
a different question. For example, midazolam was chosen as a drug that
undergoes extensive first pass intestinal wall metabolism and hepatic
CYP3A4 metabolism, and ZK253 for its low oral bioavailability. The companies
sponsoring the study (eg, Eli Lilly, Roche, Servier and Schering) did
not want to be accused of choosing easy drugs that lent themselves to
microdosing.
Professor Rowland reported that, overall, the results were promising.
The kinetics of diazepam and midazolam were not affected by the therapeutic
dose, and the microdosing
results were comparable to population kinetic data for the two drugs.
For ZK253, microdosing confirmed the low oral bioavailability seen in
conventional pharmacokinetic studies that had led Schering to halt development
of the drug.
For warfarin, which is known to have low clearance, the oral microdose
data were within the published range, but there was a difference in the
disposition kinetics compared with the therapeutic dose, suggesting saturation
of a high affinity, low capacity binding site. The
results for erythromycin were inconclusive owing to instability of the
oral microdose
solution in the gastrointestinal tract.
Professor Rowland concluded that the data were encouraging and suggested
that when used appropriately microdosing, coupled with AMS, offers a
promising tool for candidate selection at an early stage of drug development.
However, more data on a wider range of compounds will be needed to clarify
the uses and limitations of the approach. Whether or not the pharmaceutical
industry will be quite so easily convinced remains to be seen. However,
GlaxoSmithKline, having experimented with AMS with Xceleron over the
past eight years, has now invested in two state-of-the-art AMS machines
of its own, one in the UK.
Professor Wilding explains that, to date, it has been the biotechnology
companies, which can least afford to waste valuable R&D resources,
rather than big pharmaceutical companies, that have embraced microdosing. “The
bigger companies are good at doing what they have always done and tend
to be slow to change. They also tend to have more leads than the smaller
companies and can
afford to speculate. But even they realise that the numbers of new drugs
that are emerging do not add up against the increasing costs of R&D,” he
pointed out. Professor Wilding
believes that the recent decision of the US Food and Drug Administration
to follow the European lead in issuing guidance on the preclinical requirements
needed to support phase 0 studies could be the turning point for microdosing.
Other high-sensitivity techniques are also in development to rival AMS
as the technology of choice to accompany microdosing. There is also talk
of cassette microdosing
(administering microdoses of cocktails of drugs) to provide an early
insight into how drugs might work together and what interactions might
emerge.
As Professor Rowland pointed out at the conference, microdosing is not
a panacea for all the pharmaceutical industry’s R&D woes but
it could aid some of the “stop or go” decisions that all
companies must make during the early stages of drug development, which
can prove so expensive if the decision is wrong.
Correction
The dose of radioactivity above which Administration of Radioactive Substances Advisory Committee approval is required 0.1mSv, not 1mSv. |
|
The
Pharmaceutical Journal