Anti-clotting drug may hinder action of Tamiflu

Nov 9, 2006 (CIDRAP News) – A laboratory study indicates that the antiplatelet drug clopidogrel (Plavix) may limit the action of the antiviral oseltamivir (Tamiflu), which could mean trouble for cardiovascular disease patients who contract influenza.

The study by a team from the University of Rhode Island suggests that people taking clopidogrel to prevent heart attack or stroke may get little benefit from oseltamivir. The team found that clopidogrel reduced an initial step in the metabolization of oseltamivir up to 90% when the drugs were present in equal concentrations, according to the study, published in the Journal of Pharmacology and Experimental Therapeutics.

"Concurrent use of both drugs would inhibit the activation of oseltamivir . . . thus making this antiviral agent therapeutically inactive," said senior author and pharmacy professor Bingfang Yan in a University of Rhode Island news release.

However, it's not known whether the drug interaction observed in the lab study would occur to the same extent in the human body, according to others, including a spokesman for Roche, the manufacturer of Tamiflu.

Oseltamivir, a neuraminidase inhibitor, is used to treat seasonal flu and is both the first-choice drug for treating people infected with H5N1 avian influenza and the best hope for treatment if H5N1 evolves into a pandemic strain. It must be given within the first 48 hours of symptom onset to be effective. Clopidogrel is used widely to prevent heart attack and stroke in patients who have already had such an episode or have peripheral arterial disease.

Oseltamivir must first be hydrolyzed (split into fragments by reaction with water) to be active in the body, according to the report. The researchers report that a liver enzyme called HCE1 is a key factor in the hydroloysis of both oseltamivir and clopidogrel. 

The scientists induced human embryonic kidney cells to produce HCE1, exposed the cells to high-frequency sound, and used a centrifuge to remove the cell debris, their report says. Then they added varying amounts of oseltamivir and clopidogrel to the remaining liquid and assessed the hydroloysis of oseltamivir.

When clopidogrel and oseltamivir were present in equal concentrations of 50 micromoles per liter, hydrolysis of oseltamivir was reduced by up to 90% compared with the level in the absence of clopidogrel. When the concentration of clopidogrel was only 10% that of oseltamivir, it still reduced hydrolysis of the antiviral by 55%, according to the report.

Given the widespread use of clopidogrel, it is likely that oseltamivir and clopidogrel are used concurrently in some patients, the report states. The findings suggest that those who receive both drugs at the same time remain susceptible to flu if they are not yet infected or, if they are infected, can spread it to others, the authors say.

"Now we need to study the effects of the combination in human trials," Yan said in the news release. He has notified the US Food and Drug Administration and the National Institutes of Health of his findings.

Louis M. Mansky, director of the University of Minnesota's Institute for Molecular Virology in Minneapolis, said the findings warrant further study to see if the drug interaction would occur in the human body as it does in the laboratory.

"The study is interesting and suggests that Plavix can prevent metabolic conversion of Tamiflu to the active drug," Mansky told CIDRAP News by e-mail.

"The main limitation is that it's unclear how well this finding translates into a clinical situation (ie, it might not be as concerning, as the inhibition of Tamiflu conversion might not be as great)," he said.

"Observations in cell culture don't always translate perfectly when analyzed in clinical studies," Mansky added. "The only way to know for sure is to extend these studies, which I think is warranted and worth doing."

Terence J. Hurley, a US spokesman for Roche, manufacturer of Tamiflu, said the study by itself does not prove there is a clinically relevant interaction between clopidogrel and oseltamivir.

"Roche has made a preliminary review of this publication and concludes that the authors extrapolate their findings beyond the scope of the study," Hurley told CIDRAP News by e-mail. "The clinical conclusions are made based on in vitro data from a limited dataset. Neither the limitations of the in vitro study nor the clinical relevance of concentrations evaluated were discussed."

He added that Roche plans to conduct a full evaluation of the study and will provide the results to regulatory agencies if any significant concerns are identified.

Shi D, Yang J, Yang D, et al. Anti-influenza viral prodrug oseltamivir is activated by carboxylesterase HCE1 and the activation is inhibited by anti-platelet agent clopidogrel. J Pharmacol Exper Ther 2006; early online publication Sep 11 [Abstract]

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