Microdosing shows its mettle in cancer study
Wednesday, April 29, 2009
Newly-released data has added additional weight to the evidence for microdosing studies as a means to predict whether or not a candidate drug should be taken onto further development.
Microdosing, or phase 0 studies, involve dosing volunteers or patients with a drug candidate at a dose too low to have therapeutic activity - and hopefully any safety concerns - but high enough to provide valuable data relating to pharmacological dose absorption, metabolism, distribution and elimination (ADME) and pharmacokinetic (PK) outcomes.
The aim is to provide enough data to provide a 'go' or 'no go' decision on a medicine in less time than would be required using conventional animal and phase I human testing.
The latest study, reported online on the Journal of Clinical Oncology website, was a first-in-human study of Abbott Laboratories' experimental cancer drug ABT-888 in patients with advanced malignancies.
The phase 0 study was the first time that the agent was tested in humans but - just five months after the study started - the researchers said they were able to obtain "pivotal biochemical and pharmacokinetic data that ... guided the design of subsequent phase I trials of ABT-888 in combination with DNA-damaging agents".
This is an "alternative paradigm for early drug development in oncology," according to the authors, from the US National Cancer Institute (NCI). The trial was approved under the US Food and Drug Administration's Exploratory Investigational New Drug (IND) programme, which came into effect in January 2006.
ABT-888 is an inhibitor of poly (ADP-ribose) polymerase (PARP), an enzyme which plays a critical role in the repair of damaged DNA. The rationale for the treatment is that giving a PARP inhibitor along with chemotherapy drugs that damage DNA could improve the effectiveness of those drugs.
In the study ABT-888 was administered as a single oral dose of 10mg, 25mg or 50mg to 13 patients. The team analysed the effect of the drug on PARP activity in tumour biopsies and blood cells using a novel statistical method and found that the two higher doses managed to block the activity of the enzyme.
"For the past several decades there has been a low success rate of new therapies for the treatment of cancer. This has necessitated re-evaluation of the standard anticancer drug development paradigm," commented Dr Shivaani Kummar, who led the research team.
"Phase 0 trials will be a key part of a new approach," he added.
Microdosing is still an emerging technology but evidence for its usefulness has been building for some time.
Supporters of microdosing claim the technique can identify compounds likely to fail earlier and avoid wasted time and resources. It is estimated that poor pharmacokinetic data is a significant factor behind the emergence of efficacy or safety issues later in development and could be behind up to 40% of compound failures in the clinic.
A Frost & Sullivan report said in February that microdosing "might become an imperative phase of the drug development process in the years to come".
F&S analyst V. Sriram said: "The compelling advantages of microdosing present it as a potential remedy for big pharma's maladies regarding declining returns from investments in drug development."
Phil Taylor
pharmafocus@wiley.com
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