DTC and dangerous interactions	May 2009

By Steven Niles

One scientist makes the case that by driving prescriptions of newly approved drugs with limited clinical experience, DTC advertising may be increasing the risk of dangerous drug-drug interactions.

Drug-drug interactions are an epidemic, causing morbidity and mortality, especially among elderly patients dependent on a variety of medications for multiple ailments. But is direct-to-consumer advertising part of the problem? Yes, says Chris Bode, Ph.D., VP corporate development, Absorption Systems LP (absorption.com), an authority on the way that the body processes drugs. The company has also been recognized by FDA for its expertise in the Biopharmaceutics Classification System – FDA's guidance on predicting intestinal drug absorption – and advises FDA on the subject.

Drug-drug interactions are dangerous because of their potential to alter the efficacy and/or safety profiles of approved drugs by induction or inhibition of enzymes affecting the absorption, distribution, metabolism, and excretion of one of the drugs. According to Dr. Bode, if FDA did not have to police DTC advertising, the agency would have more resources, in terms of money, people, and time, to review new drug applications and abbreviated new drug applications. Dr. Bode believes that the drug companies could also better apply their resources toward researching drug-drug interactions if less money were being funneled to DTC advertising.

But the most direct link he sees between DTC and the dangers of drug-drug interactions is the fact that most of the ads driving patients to visit their doctors are for new drugs, for which clinical experience is relatively limited.

“People go to their doctor to get a drug they have, one, read about or seen on TV and, two, think they need because they have self-diagnosed based on Internet searches,” Dr. Bode told Med Ad News. “They don't know if the drug will work better than what they may currently be taking (or at all) for a given condition, and they don't pay attention to the myriad disclaimers, which may not include potential drug-drug interactions. This is made all the more dangerous by multiple medications prescribed by multiple doctors, none of whom talk to each other, and the lack of a personal relationship with a pharmacist, who used to be the final and most reliable checkpoint.”

According to Dr. Bode, the industry is much better at predicting potentially harmful drug-drug interactions with in vitro tests than it was 15 or 20 years ago, but it is not realistic to expect that developers can identify all of the possible interactions before a drug gets into late-stage clinical trials.

“Even then, the total number of people who are exposed to a drug in clinical trials is so small that a problem might not show up until after a new drug gets approved and is marketed,” Dr. Bode says. “Clinical trials should get better, because advances in pharmacogenomics and personalized medicine will help to identify potentially at-risk individuals that can be included in clinical trials. Until then (and even after), pharmacovigilance (post-marketing surveillance and reporting of adverse events) will be critically important to ensure drug safety.”

In September 2006, FDA issued a “Draft Guidance for Industry Drug Interaction Studies - Study Design, Data Analysis, and Implications for Dosing and Labeling.” The purpose of the draft guidance was for FDA to express its views and update guidance in this area. The agency states that “the metabolism of an investigational new drug should be defined during drug development and that its interactions with other drugs should be explored as part of an adequate assessment of its safety and effectiveness.”

Dr. Bode believes that in vitro studies should help to guide the design of clinical trials by identifying new chemical entities for which drug-drug interactions might be a clinical concern.

“We are pretty good now at identifying instances where we should be concerned about metabolism-based interactions,” Dr. Bode says. “But our level of understanding is such that we can only make qualitative predictions...we are not very good at predicting, quantitatively, how much the plasma concentration of a drug will change when it is co-administered with another drug that inhibits or induces the metabolism of the first drug. And our understanding of transporter-based interactions is still pretty poor, so we can't even make qualitative predictions very well, although the draft guidance tells us that we should.”

Numerous potential places – different proteins, located in different places in the body – exist where drugs can interact. Scientists could study them systematically, however, with suitable reagents, such as an in vitro assay or selective pharmacologic probes. For the most part, researchers have adequate tools to study metabolism-based drug-drug interactions, but to a large degree they are lacking for transporters.

“In terms of the number of possible other drugs that any given drug could interact with, it isn't feasible to test all of them,” Dr. Bode says. “But we don't have to because we can say, e.g., that Drug X, which inhibits CYP3A4 (the major drug-metabolizing enzyme in the liver), should not be administered with (or may require dose adjustment for) substrates of CYP3A4. In other words, we can identify class effects. But that doesn't help the public at all and may not be that useful to physicians without a resource that lists, for example, all drugs that are substrates of CYP3A4.”