Because of undetected toxicity problems, about a third of prescription drugs approved in the U.S. are withdrawn from the market or require added warning labels limiting their use. An exceptionally sensitive toxicity test invented at the University of Utah could make it possible to uncover more of these dangerous side effects early in pharmaceutical development so that fewer patients are given unsafe drugs.
To prove the point, the U researchers ran their test on Paxil, an antidepressant that thousands of pregnant women used in the years before it was linked to an increased risk of birth defects. The U.S. Food and Drug Administration now requires a warning about use in the first trimester of pregnancy. In the U study, mice exposed during development experienced multiple problems: males weighed less, had fewer offspring, dominated fewer territories and died at a higher rate. Females took longer to produce their first litters, had fewer pups and pups that were underweight. The drug doses were relatively close to those prescribed for people. In the conventional animal safety testing reported by the drug’s manufacturer, no reproductive side effects emerged until rodents took doses multiple times higher than those given to treat depression.
“We are seeing effects at a dose that is close to human levels. And we are doing it exactly the way we need to determine if it presents a risk of harm to a developing fetus,” says University of Utah biologist Shannon M. Gaukler, the study’s lead author who recently completed a doctoral degree at the U. The study will be published in the January-February issue of Neurotoxicology and Teratology, which has posted a preprint online.
University of Utah biology professor Wayne K. Potts, the study’s senior author, says that detecting toxicity problems early in preclinical testing would not only protect patients from exposure to unsafe drugs, but also help pharmaceutical companies avoid wasting billions of dollars bringing drugs to market only to have them fail.
“If we can find these health problems early on in preclinical testing, it has the potential of saving them a lot of money,” Potts says.
The key to the test’s sensitivity is the way it uses untamed house mice – rather than docile, inbred laboratory strains – and subjects them to a relentless, Darwinian competition for food, shelter and mates much like they would face in the wild. Mice jostle and race for a place in a roughly 300-square-foot pen divided into six territories by wire fencing that individuals must climb to invade or flee neighboring turf. Four of the territories are prime real estate with multiple hidden nesting sites and direct access to feeders. Two territories are poor, offering only open nesting sites and indirect feeder access. The test is called the organismal performance assay, or OPA.
Gaukler and Potts conducted the study with James Ruff, Tessa Galland, Kirstie A. Kandaris, Tristan K. Underwood, Nicole M. Liu, Elizabeth L. Young, Linda C. Morrison and Garold S. Yost. The project was funded primarily by the University of Utah’s Technology Commercialization Program.