Date: Jul 12, 2013 Author: Celia Henry Arnaud Source: Company Data (
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Subtherapeutic doses in drug development tests have shown important—but unanticipated—advantages
By Celia Henry Arnaud
When microdosing was the next big thing—back in the early to mid-2000s—drug developers had great plans for it. One of the problems with drug development is that failures often happen late in the development process. Microdosing offered a way to identify potential failures earlier, before full-fledged clinical trials. Researchers would give subtherapeutic doses to humans after minimal animal testing and use those doses to figure out how the drug behaved in the body. If the drug didn’t behave as desired, they would move on to the next candidate and save themselves the trouble of doing extensive safety testing.
Some industry observers predicted that microdosing would become a standard part of the drug development process. It would give them greater confidence in the candidates that advanced to clinical trials. At that point, they could do the safety testing required for therapeutic doses, secure in the knowledge that they had a winner.
But those plans didn’t work out quite as expected. Microdosing still has a place in the drug development process, but it’s being used in ways that people didn’t anticipate.
Today microdoses—defined as 1% of a pharmacologically active dose but no more than 100 μg—are used primarily in two types of studies. Absolute bioavailability studies are performed in parallel with standard clinical trials to determine what fraction of the therapeutic dose actually reaches systemic circulation. And so-called Phase 0 studies are early human clinical trials designed to weed out drug failures early in the process, before the conventional safety and efficacy testing required for regulatory approval. People originally thought the industry would adopt microdosing for Phase 0 trials. Such trials do happen occasionally but not nearly to the extent that people had predicted. In contrast, microdose absolute bioavailability studies are on their way to becoming an industry norm. And other uses may be yet to come… …
… Still, Arjomand says, “we definitely are in the early days” for absolute bioavailability studies. “Some pharma companies are completely sold and are moving more and more of their compounds into this paradigm.” If regulatory authorities start requiring such studies, many more companies will have to follow the early adopters, he predicts.
Other microdosing applications could be down the road. Paul T. Henderson uses microdosing combined with AMS to determine if cancer patients are good candidates for platinum-based therapies. Henderson is a researcher at the UC Davis Medical Center and chief executive officer of Accelerated Medical Diagnostics.
For the diagnostic test, Henderson gives a patient a C-14-labeled microdose of the therapeutic one or two days before a scheduled biopsy. During the biopsy, he takes blood samples and some of the leftover biopsy material. He extracts DNA from the blood and tissue and analyzes it with AMS to see how much the drug has modified the DNA.
He and his coworkers are undertaking two clinical trials, with different drugs and patient populations, to determine the level of DNA modification that indicates a patient is a good candidate for the drug. He expects the level to be between just a few drug-DNA adducts per genome per cell.
And there’s surely more to come, Lappin says. “I think there are applications of microdosing that have yet to emerge.”
