New Tamiflu Developments



New Tamiflu Developments

By Grattan Woodson, MD, FACP

November 1, 2005

Tamiflu Politics and Commercial Considerations

Roche Pharmaceuticals sells oseltamivir under the trade name of Tamiflu®. At the present time, oseltamivir may be the only treatment option active against the H5N1 avian influenza virus strains that are currently circulating in domestic and wild fowl in Eurasia.[1] It appears quite likely that Bird Flu is rapidly adapting to our species and soon will achieve efficient human-to-human transmission, heralding the onset of the next pandemic. The World Health Organization has recommended that every country establish a stockpile of enough drugs to treat 20% of its citizens in preparation for a possible avian influenza pandemic.[2] Most of the developed nations followed the WHO recommendations but the US hesitated, preferring instead to try to develop an effective vaccine. The vaccine pathway has proven difficult and there are so many variables that in the summer of 2005 the US relented and began talks with Roche on obtaining oseltamivir supplies. They have given Roche $100 million to build a new manufacturing facility for oseltamivir in the US, which will be completed in the next few years. Reportedly, the US presently has enough Tamiflu to treat 4.5 million persons for 5 days.[3] Over the course of the pandemic, predictions are that 25% to 50% of the population will become sick.

Roche claims that orders for oseltamivir have been processed on a first come, first served basis. Secretary Leavitt of the US DHHS claims that we will have an adequate supply of Tamiflu should the need arise, but declines to answer direct questions about the issue of purchase from Roche. The wholesale cost of Tamiflu is about $25 for a 5-day treatment course (10 tablets), a price that places a Tamiflu stockpile out of reach of the less developed nations. At the present time, manufacturing capacity for Tamiflu is limited to Roche facilities and their subcontractors in Europe. Most of the G8 countries have already placed their orders with Roche and governmental demand has been so great that this product was unavailable for a while in the spring of 2005 but as of June 2005, some Tamiflu began to trickle back into the retail chain, but supplies remain tight.

The process for manufacturing oseltamivir is complex. Roche says there are backorders for millions of courses of oseltamivir. In late October 2005, the company announced new partnerships with several companies to make the drug in an attempt to meet the demand for this product. Companies in India and Taiwan recently announced that they plan to begin making oseltamivir on their own with or without the cooperation of Roche, given the nature of this emergency.

On October 27, 2005, Roche announced that it would halt all shipments of oseltamivir to North American wholesalers destined for retail outlets to stop the purchase of the drug by consumers interested in having the drug on hand for use during the pandemic. In a statement to Agence France-Presse, Darien Wilson of Roche US said, “The decision does not affect Tamiflu deliveries to the US government to build a stockpile of the drug in preparation for a possible bird flu pandemic.” Explaining why Roche took this action, Wilson said “We’ve seen recently some very large purchases at the wholesale level, companies or large entities who are possibly hoarding Tamiflu right now.” Roche plans to resume shipments to North America when the flu season begins. “We don't have a seasonal flu or pandemic right now, so in an effort to better manage the supply chain in the US we're just going to hold up any additional shipment until the time comes when there is a seasonal outbreak,” she explained.

Oseltamivir treatment of influenza

Tamiflu works best if it is taken early in the course of the disease symptoms (within the first 48 hours of the illness). It might be useful even if started later but this is not established. I plan to administer it to very sick patients no matter how long they have had symptoms as long as there is hope they can survive. It is also possible to use it to prevent the flu by taking Tamiflu tablets prior to infection, during the time period when there is danger of exposure to the flu. While this prophylactic strategy works, it requires the continuous use of one tablet daily until the pandemic is past. If there is a severe shortage of Tamiflu, using the drug in this way is unwise. The strategy I plan to follow is to wait until flu symptoms are present before beginning Tamiflu treatment. The recommended dose is one tablet twice daily for 5 days.

Since half the population who contract influenza have no or only a few symptoms of the disease, even if you don’t take Tamiflu in the preventive regimen you still have a 50% chance of not getting sick. By reserving the drug for those who become ill with flu, you will be able to effectively treat a much larger number of patients than if the drug is used in its preventive mode.

Influenza Resistance to Oseltamivir

One recent development reported in May 2005 is the detection of some strains of H5N1 avian influenza that have crossed over from birds to humans in South East Asia that are developing resistance to Tamiflu. While this is a disturbing observation, it does not mean that when pandemic flu arrives here it will be totally resistant to Tamiflu treatment. This is unlikely to be the case. It is likely however that some strains of the virus will carry this resistance factor meaning that some patients infected by those strains will not respond as well to Tamiflu treatment as expected. Oseltamivir has never been used during a full-blown influenza pandemic. After treatment with oseltamivir during seasonal influenza, it is common to recover 1% to 2% of isolates that have become resistant to this drug.[4] Prophylactic use oseltamivir in Viet Nam has recently been documented to result in the development of a highly resistant H5N1 isolate.[5] In an NIH study of mice reported in the Journal of Infectious Disease infected with different H5N1 strain isolated in Viet Nam, documented considerable oseltamivir resistance.[6] Mice treated with the equivalent of the human dose for 5 days all died. To achieve only an 80% survival rate required treatment for 8 days instead of 5 days and a dose 10 times greater than the equivalent human dose. Obviously if the dose or length of time required to treat the infection is increased this reduces, in a proportional manner, the number of people that will benefit from the national stockpiles of the drug.

Using oseltamivir in combination with probenecid

While preparing a presentation on Bird Flu for his colleagues at Portland Adventist Medical Center in Oregon, Joe Howton, MD, Medical Director, Emergency Services at the hospital, ran across an obscure comment in the product information on the antiviral drug Tamiflu® used for treatment of influenza. The comment was in the section on safety and drug interactions and referred to the results of safety studies that were completed before the drug was approved for use. The finding was that when Tamiflu was given at the same time as another commonly used drug, probenecid which is used to treat gout, the blood level of Tamiflu doubled and the time it remained at effective levels in the body increased from about 8 hours to more than 20 hours.

This finding astounded Joe. He immediately realized its importance given our concerns about Bird Flu and the present severe shortage of Tamiflu. He understood that this means that if it were safe to give Tamiflu in combination with probenecid, it would increase the clinical effects of each Tamiflu tablet significantly and this would starch the available supply.

When Joe called me about this to see what I thought, at first I was a bit skeptical. Why hadn’t someone else figured this out before now? Besides gout, probenecid has been indicated for increasing penicillin blood levels and the length of time it stays in the body for years. So, it was not much of a stretch to think of it for use with Tamiflu especially since we are facing such a shortfall of this drug. So, I spent the night and much of the next on the National Library of Medicine’s web site and reading my trusty Goodman and Gilman Pharmacology Text and sure enough, Joe was right. Tamiflu levels could be increased as can the length of time it stays in the body fighting the virus by combining it with probenecid. I had used probenecid for as long as I had practiced, over 25 years now, and regarded it as a reliable old standby in my pharmaceutical armamentarium. What made this discovery all the sweeter, it is generic and relatively inexpensive at a cost of about $20 for a 10-day treatment course.

During my investigations, I discovered that infectious disease doctors worldwide were already using probenecid to increase the levels of drugs used to fight tuberculosis and HIV-AIDS, but did not find any references to using it intentionally with Tamiflu for this purpose. The way probenecid increased the effects of these drugs, including Tamiflu, is exactly the same way it increases the level and effective blood levels of penicillin. This was very reassuring. I was not too concerned that the combination of probenecid with Tamiflu was not formally approved by the any regulatory agency like the US FDA since every day, as a doctor who takes care of people, I find myself using approved drugs for “off label” indications. This is a perfectly acceptable and established practice as long as the doctor has good reason to believe that it will be of benefit to his or her patient.

In my opinion this is an important finding. We all owe Dr. Howton a debt of gratitude. While this novel combination does not solve our Bird Flu problem by any stretch of the imagination, it does mean that suddenly the world has the equivalent of two-and-a-half times more Tamiflu in the world’s stockpile now than we thought. What’s more, the Tamiflu produced from this point forward will also go two-and-a-half times further than we originally thought. Of course, this all depends on our ability to ramp up probenecid manufacture, which I believe can be accomplished rather quickly and inexpensively. On the whole, this is one of the few pieces of really good news concerning the Bird Flu pandemic that I have heard since becoming concerned about it in 2004.

Bird Flu Resistance to Tamiflu: A Cloud with a Silver Lining?

One unexpected bit of information I gleaned while researching the use of Tamiflu in combination with probenecid has to do with Tamiflu resistance. Like all antibiotics and antiviral drugs, resistance to Tamiflu has also been seen in the clinic and laboratory. With bacteria, this is usually really bad news because it makes the drug ineffective against the bug, meaning we have to find a new one that is typically more toxic and much more expensive. However, what I learned about influenza resistance to Tamiflu was not as discouraging as I expected. In fact, I think it might give us something we can exploit to lower the severity of Bird Flu infections.

This finding has to do with the way the virus has to change itself to avoid Tamiflu. The method involves a single change in one or two spots in a protein the flu bug uses to attach itself to the human cell. While making this change allows the flu to escape the effect of Tamiflu, it also partially cripples itself by making it much harder for it to infect the cell and kill it. In other words, Bird Flu without the Tamiflu resistance mutation is much more deadly than those with it. So, this may mean that Tamiflu could be useful for treatment of Bird Flu even if there is a high prevalence of Tamiflu resistant avian influenza strains in your community. The drug would be useful by selecting out the weaker members of the viral family as the ones that got through the Tamiflu defense while screening out the stronger members. This intriguing idea only holds as long as Bird Flu does not develop a new way to resist the drug. Unfortunately, this is likely. For right now though, this is an idea worth considering.

Oseltamivir scientific background information

The following is a brief overview of the pharmacology of this drug written primarily for medical professionals. It includes a lot of details that will not make much sense to most folks. I’ve already shared the important stuff with you in the proceeding paragraphs, so unless you’re a glutton for punishment, skip on to the next chapter.

Oseltamivir is a potent and highly specific neuraminidase inhibitor of type A and B influenza virus. The drug is US FDA registered for this indication with the recommended treatment course being one 75 mg tablet twice daily for five days. Clinical trials conducted using oseltamivir for treatment of type A and B seasonal influenza showed that the drug was effective if started within 2 days of onset of flu symptoms but not so if begun later. The average patient had a quicker recovery, fewer complications of flu including bacterial pneumonia requiring antibiotic therapy. Oseltamvir is also indicated for prevention of influenza with the US FDA registration dose of 75 mg once daily for up to 42 days.

Oseltamivir metabolism and excretion

After oral administration, 80% of oseltamivir is absorbed into the blood stream.[7] In patients with normal renal function, the active drug has a half-life of about 8 hours requiring twice-daily administration to maintain blood and tissues levels adequate for an effective clinical response against influenza. As the drug passes through the kidney, the active drug is excreted into the urine by two separate means.[8] The first is simple filtration by the glomerulus that is responsible for about 40% of the active drug found in the urine. The second is active secretion form by the renal tubule cells into to urine, which is responsible for 60% of the drug’s excretion.

Probenecid inhibits renal excretion of oseltamivir

Probenecid is registered with the US FDA for treatment of gout and for increasing the plasma level and half-life of β-lactam (penicillin-class) antibiotics. It has this effect on the antibiotic by inhibiting its excretion by the renal tubule cell. Probenecid is used informally to prolong the half-life of antibiotics used for treatment of tuberculosis and in treatment of HIV-AIDS to boost the plasma level of antiviral agents. Probenecid increases the plasma levels of all three drugs by inhibiting an enzyme system responsible of transporting the drug into the renal tubule. This same enzyme system is responsible for excretion of 60% of plasma oseltamivir.8 In test subjects, giving probenecid 500 mg four times daily in combination with oseltamivir resulted a doubling of plasma levels of oseltamivir. The probenecid increased the half-life of oseltamivir to about 20 hours and the area under the curve by 2.5 times the level seen with the same oseltamivir dose but without probenecid. In effect, this novel combination increases to effective stockpile of oseltamivir by 2.5 times the current level. The changes in plasma concentration and half-life of oseltamivir when used in combination with probenecid means that oseltamivir 37.5 mg (1/2 tablet) given twice daily with probenecid would achieve better pharmacologic results than oseltamivir 75 mg given twice daily without probenecid.

[pic] Hill et al., 2002.

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[1] Relenza is also a neuraminidase inhibitor and it may be effective against H5N1 in humans, but this has not been demonstrated clinically. It did reduce viral load of both oseltamivir-sensitive and oseltamivir-resistant strains of H5N1 influenza in ferrets, which were experimentally infected with virus taken from a Vietnamese girl who got bird flu, apparently from caring for her older brother, and recovered from it. [Nature 437, 1108 (20 October 2005), Avian flu: Isolation of drug-resistant H5N1 virus] Most but not all strains of H5N1 are resistant to the older antiviral drugs in the amantadine class. A vaccine designed to provide immunity against H5N1 has been produced and while clinical trials show it does induce an antibody response, there are no randomized clinical trials of this vaccine’s clinical efficacy. The vaccine was manufactured using H5N1 strains prevalent in Viet Nam in 2004. Antigenic shift has occurred since that time which might make the vaccine ineffective against the current strain.

[2] Do the math: 900 million people in the G8 countries x 20% = 180 million courses of therapy x $25 = $4.5 billion wholesale.

[3] The recommended dose is one 75 mg tablet twice daily for 5 days. So, they have 4.5 million x 10 tablets = 45 million, 75 mg tablet doses in the stockpile. It is possible that the virus may be resistant to Tamiflu by the time it makes it to the US so this may be a moot issue anyway. The present ration plan announced by CDC is that the stockpiled Tamiflu will be reserved for first responders and medical personnel. If there is not enough to go around, they plan to give it to the medical personnel only.

[4] An interesting fact concerning these oseltamivir resistant strains is that they are less infective and virulent compared with non-resistant strains.

[5] Isolation of drug resistant H5N1 influenza, 20Oct2005, Nature Vol 437, p 1108

[6] Hui-Ling Yen, Arnold S. Monto, Robert G. Webster, and Elena A. Govorkova, Virulence May Determine the Necessary Duration and Dosage of Oseltamivir Treatment for Highly Pathogenic A/Vietnam/1203/04 Influenza Virus in Mice., The Journal of Infectious Diseases 2005;192:665-672

[7] Oseltamivir phosphate is a prodrug and is not directly active against influenza. The active metabolite, oseltamivir carboxylate, is formed as a result of the prodrug being transformed by hydrolysis by hepatic carboxylase as it passes through the liver.

[8] Hill GH, Cihlar T, Oo C et al., The anti-influenza drug oseltamivir exhibits low potential to induce pharmacokinetic drug interactions via renal secretion—correlation of in vivo and in vitro studies., Drug Metabolism and Disposition 2002;30:13-19

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