Nature 438, 6 (3 November 2005) | doi:10.1038/438006a; Published online 2 November 2005

Wartime tactic doubles power of scarce bird-flu drug

Declan Butler


Use of common drug could stretch world stocks of Tamiflu.

Doctors think they have hit on a way to effectively double supplies of a drug that fights bird flu. Administering Tamiflu alongside a second drug that stops it being excreted in urine means that only half doses of the treatment would be needed.

Tamiflu (oseltamivir phosphate) is the main antiflu medicine recommended by the World Health Organization (WHO). The WHO suggests that, in anticipation of a flu pandemic, countries should stockpile enough for at least a quarter of their population. But although Swiss drugmaker Roche, the sole supplier, has quadrupled its production capacity over the past two years, the current supply is thought to cover just 2% of the world population.

Last week, Joe Howton, medical director at the Adventist Medical Center in Portland, Oregon, suggested a way to double supplies, after browsing basic safety data from Roche for a talk on avian flu.

The technique was invented during the Second World War to extend precious penicillin supplies. Scientists found that a simple benzoic acid derivative called probenecid stops many drugs, including antibiotics, being removed from the blood by the kidneys. Probenecid is readily available and is still widely used alongside antibiotics to treat gonorrhoea and syphilis, and in emergency rooms, where doctors need their patients to have high, sustained levels of antibiotics in their blood.

Howton noticed from Roche's data that Tamiflu, like penicillin, is actively secreted by the kidneys, and that the process is inhibited by probenecid. Giving the flu drug together with probenecid doubles the time that Tamiflu's active ingredient stays in the blood, doubles its maximum blood concentration, and multiplies 2.5-fold the patient's total exposure to the drug (see graph, and G. Hill et al. Drug Metab. Dispos. 30, 13–19; 2002).

In other words, you could get away with using half as much Tamiflu to get the same therapeutic effect. "It dawned on me that the data potentially represented a tremendous therapeutic benefit," Howton told Nature.

Wartime tactic doubles power of scarce bird-flu drug


Given that Roche published the probenecid data in 2002, has it considered this option? "It doesn't seem so," says Martina Rupp, a spokeswoman at Roche's headquarters in Basel. "It is an interesting idea, but we can't really say anything," she adds, claiming that there are insufficient data. The WHO and the US Food and Drug Administration declined to comment when Nature asked them about the idea.

Studies are being proposed that will look at safety issues relating to probenecid and Tamiflu, although doctors argue that there are already enough data for the drug combination to be used, even without specific approval from regulatory agencies. Grattan Woodson of the Atlanta Research Center in Decatur, Georgia, has prescribed probenecid for more than 25 years and says he prescribes drugs for such off-label purposes every day. "This is a perfectly acceptable and established practice," he says.

Peter Zed, a specialist in emergency medicine at Vancouver General Hospital in Canada, agrees. He has published studies of the safety of probenecid and antibiotic combinations. "There would be nothing unique about using probenecid with Tamiflu," he says.

Michael Osterholm, director of the US Center for Infectious Disease Research and Policy in Minneapolis, Minnesota, cautions that probenecid alone will not be sufficient to avert a flu pandemic. He points out that the most optimistic estimate of Tamiflu production capacity in the next five years gives enough to treat just 7% of the global population.

Coping with a pandemic will require "launching a worldwide Manhattan-like project for drug production, packaging and distribution today", Osterholm says. "It's not just about having a magic bullet; it's whether you can make it and find enough guns from which to shoot it." Still, doubling the doses available could be crucial for treating people quickly after an outbreak, and Osterholm says the idea definitely merits investigation.

"This is wonderful," agrees David Fedson, formerly a medical director of the vaccine company Aventis Pasteur, based in Lyons, France. "It is extremely important for global public health because it implies that the stockpiles now being ordered by more than 40 countries could be extended, perhaps in dramatic fashion." He suggests that capsules containing both Tamiflu and probenecid should be developed.

Like many scientists, Fedson is stumped by the apparent lack of interest from Roche, and the relevant authorities. "It's stupefying," he says.