Serious Drug Interactions Prevention : Discoveries After Approval

by Food and Drug Administration (FDA)

(Page 2 of 4)

Three phases of clinical trials in humans must happen before a drug can be marketed. Phase 1 studies focus on a drug's side effects and how the drug is metabolized and eliminated from the body. Phase 2 studies focus on a drug's effectiveness. And Phase 3 studies gather more information on safety and effectiveness, which includes using the drug in combination with other drugs.

"Around Phase 1 of clinical development, we look for the ability of our drug to inhibit CYP450 and we determine whether our drug causes an increase in concentration of other drugs as a result of the inhibiting," Wrighton says. "By Phase 2, we know if our drug is an inducer or an inhibitor, and we know the enzyme that metabolizes it. This tells us what patient factors and other drugs influence the metabolism of our drug."

The FDA has published two guidance documents to help drug manufacturers conduct drug-drug interaction studies. One document focuses on laboratory (in vitro) studies, and the other deals with human (in vivo) studies. The FDA is revising this second guidance on evaluation of drug interactions in humans and its labeling implications. The revision will involve several significant changes, including a proposal to use a classification system for CYP3A inhibitors in drug labeling, according to Shiew-Mei Huang, Ph.D., who chairs the FDA working group responsible for revising the guidance. The revisions will highlight key drug interactions and improve the consistency of labeling.

Researchers say there are several important variables that affect individual differences in how drugs are metabolized, including race, gender, age, and health conditions. For example, people with kidney or liver disease don't eliminate drugs from their system as well as people who are healthy. Very young children and older people have slower drug metabolism than others, and women may metabolize drugs differently than men in some cases.

Wrighton says, "CYP2D6 is worth noting because roughly 6 percent to 8 percent of Caucasians don't have an active form of that enzyme." CYP2D6 metabolizes many cardiovascular and neurologic drugs. The CYP2C19 enzyme is absent in 20 percent to 30 percent of Asians. This enzyme metabolizes anticonvulsants, Valium (diazepam), and several tricyclic antidepressants.

"We are rapidly using genetics to predict drug toxicity and we want research to become even more targeted and specific," says Flockhart. "We want to identify the people who are vulnerable to the really bad things."

Watkins says there also needs to be more research on enzymes other than CYP450. "There is also increasing attention on drug interactions happening through "transporters," which control how drugs are taken up by the liver and pumped into the bile," he says. Bile is fluid that is secreted by the liver to aid in digestion.

Over the last several years, there has been a substantial increase in the number of drug-interaction studies the FDA sees in new drug applications. If drug interactions are significant enough, they can prevent a drug from being approved by the FDA. If the agency determines that known drug interactions can be managed and that a drug's benefits outweigh the risks for the intended population, a drug will be approved. Drug-interaction information then goes into the drug's labeling in the sections on "clinical pharmacology," "precautions," "warnings," "contraindications," and "dosage and administration."

Discoveries After Approval

Monitoring drug interactions after a drug is approved is a critical component of FDA oversight. The Seldane case, according to agency experts, is a perfect example of how reports of adverse events can uncover interactions that hadn't been anticipated earlier.

Because of the practical size of clinical trials, a drug's safety profile is not fully complete until a drug gets out in the wider market. Most drugs approved by the FDA are studied in a few thousand people, and a rare problem might not become apparent until 100,000 people are exposed to the drug. While the number of people in clinical trials is increasing in some areas of drug development, and researchers are getting better at predicting the rare events, it's not always possible to identify every risk of drug interactions.

Besides Seldane, three other drugs have been taken off the market because of significant interactions with other drugs — a heart drug called Posicor (mibefradil), the antihistamine Hismanal (astemizole), and the heartburn drug Propulsid (cisapride).

But it is rare that problems with drug interactions cause the FDA to reassess a drug's approval. The more usual case is that new information on drug interactions is added to the drug's labeling and doctors are informed through letters and other warning announcements. Then it takes time to evaluate additional reports and assess how well the labeling changes are working.

For example, in March 2001, the FDA advised women taking the prescription blood thinner warfarin to consult a doctor or pharmacy before using miconazole, an over-the-counter (OTC) antifungal drug for vaginal yeast infections. Manufacturers of vaginal creams and suppositories containing miconazole had to add a warning to the label that bleeding and bruising may occur in people taking the two drugs.

About the Author

www.fda.gov
FDA is A United States government body that oversees medical devices, including contact lenses, intraocular lenses, excimer lasers and eyedrops. In the US, these products must be approved by the FDA before they can be marketed.