Herb/Drug Interaction Research Could Include Clinical, Behavioral Studies

Future research on herb/drug interactions could range from clinical trials of botanicals to behavioral studies of consumer use patterns, according to speakers at an American Society of Clinical Pharmacology & Therapeutics workshop in Bethesda, Md. July 22-23.

Drug interactions with herbal products that target menopausal women should be of particular interest, FDA Office of Drug Evaluation V Director Jonca Bull, MD, said. The controversy surrounding hormone replacement therapy likely will "diminish the trust in the established medical community with women" and lead to a rise in sales of natural alternatives, she predicted.

"I think the dietary supplement area, because they are naturally and presumptively better, is going to be of increasing interest" to women, Bull said. She noted the increasing use of botanicals could lead to a higher potential for drug interactions.

A report sponsored by NIH concluded that, according to recent studies, HRT offered little or no measurable protection against diseases such as osteoporosis and Alzheimer's, but potentially increased the risk of breast cancer in women.

In anticipation of what may be a burgeoning demand for alternative therapies, the supplement industry has already begun to step up promotions for botanicals, such as black cohosh and red clover, as a safer means of menopausal symptom relief.

Other areas where herb/drug interactions are a concern were also discussed by ASCPT workshop participants.

Peter Honig, MD, Merck Research Labs, suggested further research be conducted to determine what percent of patients fail to discuss their herbal supplement use with physicians. The information could help FDA learn how to successfully communicate the risks of herb/drug interactions, he said.

With many patients unable to "recall the names of the drugs they are on...I would imagine that they are very poor at providing [physicians] an accurate herbal history or dietary supplement history," Honig said.

The former director of FDA's Office of Drug Safety additionally challenged workshop attendees to study the reasons herbal product use is withheld from physicians. Honig noted one reason the information is withheld could be out of concern that practitioners will be upset after learning about patients' self-medication decisions.

Honig suggested behavioral research could additionally investigate why physicians often fail to follow established clinical practice guidelines. With regard to recommendations concerning herbal products, he pointed out one major reason is simply that, while physicians are often aware of the guidance, "they do not agree with what it says."

In general, though, doctors need to be better educated about potential herb/drug interactions, Honig said. For example, he posited the majority of practitioners are unaware of how St. John's wort interacts with drugs metabolized along the CYP3A4 pathway.

Despite what Honig characterized as widespread ignorance of St. John's wort's interaction potential, extensive research has been conducted. Moreover, different approaches regarding how to label Rx drugs metabolized on the CYP3A4 pathway is under investigation by FDA's St. John's wort working group.

One step the group has taken is to contract with researchers at Indiana University School of Medicine to "assess the full spectrum of clinical implications" posed by the botanical's interaction with various prescription drugs, FDA Center for Drug Evaluation & Research Office of Clinical Pharmacology & Biopharmaceutics Deputy Director for Science Shiew-Mei Huang, PhD, said.

Two of the studies, led by Stephen Hall, PhD, measured the effect of St. John's wort on cytochrome P450 and P-glycoprotein activity.

One of the trials examined how St. John's wort and fexofenadine (Aventis' Allegra ) interact. In the study, each volunteer initially took 60 mg fexofenadine, then several days later took the same dose along with 900 mg St. John's wort. Participants then took the botanical alone each day for roughly two weeks.

Describing the study, Hall noted Allegra's bioavailability depended on the duration of St. John's wort administration, increasing after acute dosing of the botanical and decreasing in response to chronic dosing.

Some medications already carry warnings against concomitant use with the botanical. Huang pointed out that, upon approval, labeling for Danco Labs' abortifacient Mifeprex , Abbott Labs' protease inhibitor Kaletra and Novartis' cancer drug Gleevec had to carry warnings about St. John's wort use.