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Biomedicine

Scanning for Drugs

An older technology re-envisioned could lower the cost of drug R&D – and make it more humane.

Medical researchers are discovering a wide range of new uses for imaging technology – applications that may soon accelerate drug development, lower clinical testing costs, and reduce the number of animals used in pre-clinical studies.

In particular, positron emission tomography (PET) and biophotonic scanning are enhancing research areas that seek to cure human diseases.

PET scanners, first developed over 30 years ago, have been used mainly to identify fast-growing cancers in humans and to track the progress of drug therapies. Today, the technology has broadened into a non-invasive process for studying the living tissue of mice, primates, and other animals in early stage drug trials – without having to destroy the animal subjects, according to Michael Welch, co-director of the division of radiological sciences at Washington University’s Mallinckrodt Institute of Radiology in St. Louis.

Imaging technology experiments typically work this way: Researchers inject a microdose (measured in micrograms) of a drug, which is tagged with a radioactive substance that emits positrons. Then the subject is placed inside a PET scanner to monitor the drugs as they travel through the body. The primary benefit of these scans: drug makers can see if test drugs reach the proper destinations, an important step in early tests.

According to Welch, researchers can now use smaller and safer amounts of drugs and verify that the drug is successfully interacting with a target protein receptor on the surface of a cell; they can find these answers in fewer trials; and they can conduct these experiments with fewer animal subjects.

And this is good news for pharmaceutical companies, too, since they could lower the cost of developing a drug from more than $100 million to the tens of millions of dollars by identifying early delivery problems with newly developed drugs, according to David Rollo, chief medical officer of PET scanner manufacturer Philips Medical Systems.

Because a PET scanner can track the progress of a drug to its intended target in small amounts that quickly dissipate, it enables a single subject to act as its own control group during pre-clinical experiments, according to Rollo, rather than using many animals to obtain the same statistically significant data.

“The half-life of the agents [drugs] can be seconds [or] minutes, so you can bring back the animal the next day for another round of testing,” Rollo says.

Simon Cherry, director of the Center for Molecular and Genomic Imaging at the University of California at Davis, says PET scanners can reduce the amount of animal testing by “killing off a number of drugs tested in pre-clinical evaluations.” Drugs that don’t reach their intended targets when injected into animals can be identified by PET scanners, eliminating the need for subsequent tests.

Cherry says the approximately 125 animal PET scanners currently in use in the United States are located at the largest pharmaceutical companies and research facilities, since they’re too expensive for many smaller laboratories. If the price of animal PET scanners – which cost around $500,000 – dropped to $100,000, smaller laboratories could begin to integrate imaging tests into its process, which could help replace auto-radiography studies that require killing animals and viewing thin slices of their cells, according to Cherry.

PET imaging isn’t the only alternative for pre-clinical tests. Biophotonic imaging is similar to PET scanning in its ability to streamline animal testing. Instead of tiny radioactively tagged drugs, though, it uses a charge coupled device camera (CCD) to track agents that have been tagged with a bioluminescent protein from, for instance, a firefly that emits light, according to Pam Contag, president and co-CEO of imaging company Xenogen.

“We believe that animal [studies] at the molecular level will yield more predictive data about the drugs that [companies] are considering putting into the market,” says Contag.

Pharmaceutical companies can use imaging to more quickly identify drugs that would fail in clinical evaluations, Contag says, which can save millions of research dollars. “Fail fast and fail early,” Contag says, adding that companies may test up to 100 variations of a drug before coming out with a product.

Despite the potential advantages of imaging technology, though, Contag says pharmaceutical companies continue to use conventional animal-testing processes, because to move a new drug through the approval process, they must provide data to the Food and Drug Administration (FDA) that is based upon more than one testing and measurement method.

And the drug companies believe that if they rapidly adopt imaging methodologies, they will be required by regulatory agencies such as the FDA to perform new imaging experiments in addition to the current animal tests, according to Jarrod Bailey, a project development coordinator at the University of Newcastle and a member of the Physicians Committee for Responsible Medicine.

While that challenge – searching for more cost-effective and ethical testing methods while also satisfying the FDA – has proven to be a difficult one for pharmaceutical companies, they are experimenting with imaging processes.

Hong Zhang, a research scientist at Vertex Pharmaceuticals, says conducting experiments with Xenogen’s imaging technology can reduce the number of animals used by 75 percent and yield more accurate results about whether a particular drug is reaching its intended target. Zhang says that imaging “allows us to dynamically follow an animal and study the progression of a disease from 24 to 48 to 72 hours.”

However, Vertex continues to use invasive surgical procedures that require destroying animal subjects in order to conduct traditional experiments, particularly those that measure one point in time, as opposed to experiments that track drug tests over an extended period.

“The sensitivity [of measuring through imaging] is limited compared to traditional techniques,” Zhang says.

In the near future, though, Bailey, along with many other researchers, believes that imaging technologies will become a more effective –and humane – tool for early-stage drug trials.

“PET scanning is exactly what the doctor ordered,” says Bailey.

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