Oseltamivir
Encyclopedia
Oseltamivir INN
(icon), an antiviral drug
, slows the spread of influenza
(flu) virus between cells in the body by stopping the virus from chemically cutting ties
with its host cell; median time to symptom alleviation is reduced by 0.5–1 day. The drug is sold under the trade name
Tamiflu, and is taken orally in capsules or as a suspension. It has been used to treat and prevent influenza A virus and influenza B virus infection in over 50 million people since 1999.
Oseltamivir is a prodrug
, a (relatively) inactive chemical which is converted into its active form by metabolic process after it is taken into the body. It was the first orally active neuraminidase inhibitor
commercially developed. It was developed by C.U. Kim, W. Lew, and X. Chen of US-based Gilead Sciences
, and is currently marketed by Hoffmann–La Roche (Roche). In Japan, it is marketed by Chugai Pharmaceutical Co.
, which is more than 50% owned by Roche.
, the World Health Organization
(WHO) reported 314 samples of the prevalent 2009 pandemic H1N1 flu
tested worldwide have shown resistance to oseltamivir.
, it is converted by natural chemical processes, hydrolysed
hepatically to its active metabolite, the free carboxylate
of oseltamivir (GS4071).
Oseltamivir is a neuraminidase inhibitor
, serving as a competitive inhibitor towards sialic acid
, found on the surface proteins of normal host cells. By blocking the activity of the viral neuraminidase (NA) enzyme, oseltamivir prevents new viral particles from being released by infected cells.
Oseltamivir is indicated for the treatment and prevention of infections due to influenza A and B viruses.
Oseltamivir is approved for use in persons age one and over. There is also currently an FDA Emergency Use authorization temporarily allowing the use of Tamiflu in children less than one year old. The usual adult dosage for treatment of influenza is 75 mg twice daily for five days, beginning within two days of the appearance of symptoms, with decreased doses for children and patients with renal impairment. It may be given as a preventive measure either during a community outbreak or following close contact with an infected individual. Standard prophylactic dosage is 75 mg once daily for patients aged 13 and older, which has been shown to be safe and effective for up to six weeks. The importance of early treatment is that the NA protein inhibition is more effective within the first 48 hours. If the virus has replicated and infected many cells, the effectiveness of this medication will be severely diminished, especially over time.
The Centers for Disease Control and Prevention
(CDC) recommends physicians prioritize which patients to whom they prescribe oseltamivir: specifically, people hospitalized with more severe illness, children younger than two years old, adults over 65, pregnant women, people with certain chronic medical or immunosuppressive conditions and adults under 19 on long-term aspirin
therapy. However, they also advise children and adults presenting with suspected flu who have symptoms of lower respiratory tract illness or clinical deterioration should also receive prompt empiric antiviral therapy, regardless of previous health or age.
The standard recommended dose incompletely suppresses viral replication in at least some patients with H5N1
avian influenza, increasing the risk of viral resistance and rendering therapy less effective. Accordingly, higher doses and longer durations of therapy have been suggested for treatment of patients with the H5N1 virus.
Clinical trials for an increased dosage began in May 2007. All avian influenza cases in Indonesia, Thailand, and Vietnam were inducted into the trial. The trial also included 100 cases of severe seasonal influenza from each of those countries and the United States. Half received the current standard dose, and half received a double dose, but for the standard length of time.
has been suggested as a method to extend a limited supply of oseltamivir. Probenecid reduces renal excretion of the active metabolite of oseltamivir. One study showed that 500 mg of probenecid given every six hours doubled both the peak plasma concentration (Cmax) and the half life of oseltamivir, increasing overall systemic exposure (AUC) by 150 percent. Although the evidence for this interaction comes from a study by Roche, it was publicized only in October 2005 by a doctor who had reviewed the data. Probenecid was used in similar fashion during World War II
to extend limited supplies of penicillin
. It is still used to increase penicillin concentrations in serious infections.
, which reviews medical evidence, in a review published in the British Medical Journal
, announced it had reversed its previous findings that the antiviral drug Tamiflu can ward off pneumonia and other serious conditions linked to influenza. They reported an analysis of 20 studies showed Tamiflu offered mild benefits in terms of duration of symptoms for healthy adults if taken within 24 hours of onset of symptoms, but found no clear evidence it prevented lower respiratory tract infections or other complications of influenza. These findings relate only to its use in healthy adults with influenza, not in patients judged to be at high risk of complications. Tamiflu may still be a useful drug for reducing the duration of symptoms, although for this use it still has yet to be compared with NSAID
s or paracetamol
.
Common adverse drug reaction
s (ADRs) associated with oseltamivir therapy (occurring in over 1% of clinical trial participants) include: nausea, vomiting, diarrhea, abdominal pain, and headache. Rare ADRs include: hepatitis
and elevated liver
enzyme
s, rash, allergic reactions including anaphylaxis
, and Stevens–Johnson syndrome.
Various other ADRs have been reported in postmarketing surveillance, including: toxic epidermal necrolysis
, cardiac arrhythmia, seizure, confusion, aggravation of diabetes, and haemorrhagic colitis
.
There are concerns that oseltamivir may cause dangerous psychological, neuropsychiatric side effects including self harm in some users. These dangerous side effects occur more commonly in children than in adults. This stems from cases in Japan, where the drug is most heavily prescribed, consuming 60% of the world's production. Concern has focused on teenagers, but problems have also been reported in children and adults.
In March 2007, Japan's Health Ministry warned that oseltamivir should not be given to those aged 10 to 19. The Ministry had previously decided, in May 2004, to change the literature accompanying oseltamivir to include neurological and psychological disorders as possible adverse effects, including impaired consciousness, abnormal behavior, and hallucination
s.
According to Japan's Health Ministry, between 2004 and March 2007, fifteen people aged 10 to 19 have been injured or killed by jumps or falls from buildings after taking oseltamivir, and one 17-year-old died after he jumped in front of a truck. A renewed investigation of the Japanese data was completed in April 2007. It found that 128 patients had been reported to behave abnormally after taking oseltamivir since 2001. Forty-three of them were under 10 years old, 57 patients were aged 10 to 19, and 28 patients were aged 20 or over. Eight people, including five teens and three adults, had died from these actions.
In October 2006, Shumpei Yokota, a professor of pediatrics at Yokohama City University, released the results of research involving around 2,800 children which found no difference in the behavior between those who took oseltamivir and those who did not. Chugai Pharmaceutical Co.
(which produces oseltamivir in Japan) gave Yokota's department 10 million yen (about US$105,000) over five years.
To determine whether to lift the 2007 ban, a research team from the Japanese Health, Labour and Welfare Ministry studied 10,000 children under the age of 18 who had been diagnosed with influenza since 2006. The study was finalized in April 2009. Taking into account all degrees of abnormal behavior, including minor behavioral problems such as incoherent speech, the study found children who took oseltamivir were 54 percent more likely to exhibit abnormal behaviour than those who did not take the drug. When the team limited its analysis to children who had displayed serious abnormal behavior that led to injury or death, it found those who had taken oseltamivir were 25% more likely to behave unusually.
In November 2006, the United States Food and Drug Administration
(FDA) amended the warning label to include the possible side effects of delirium
, hallucinations, or other related behavior. This went further than the FDA's previous pronouncement, from a year before, that there was insufficient evidence to claim a causal link between oseltamivir use and the deaths of 12 Japanese children (only two were from neurological problems, although more have died since then). The change to a more cautionary stance was attributed to 103 new reports the FDA received of delirium, hallucinations and other unusual psychiatric behavior, mostly involving Japanese patients, received between August 29, 2005 and July 6, 2006. This was an increase from the 126 similar cases logged between the drug's approval in 1999 and August 2005.
Roche points out that oseltamivir has been used to treat over 50 million people since 1999, and states the influenza may itself cause psychological problems.
In March 2007, the European Medicines Agency said that the benefits of oseltamivir outweighed the costs, but that it would closely monitor reports from Japan.
In April 2007, South Korea issued a safety warning against prescribing oseltamivir to teenagers except in special cases.
A joint investigation by the British Medical Journal (BMJ) and British TV Channel 4 published in the BMJ on December 8, 2009 concluded that in otherwise healthy adults they "have no confidence in claims that oseltamivir reduces the risk of complications and hospital admission in people with influenza" and believe it should not be used in routine control of seasonal influenza. There was also concern about underreporting of side effects of the drug. In contrast, according to the BMJ, Roche has stated in media briefings that oseltamivir reduced hospital admissions by 61%; secondary complications (including bronchitis, pneumonia, and sinusitis) by 67% in otherwise healthy individuals and lower respiratory tract infections requiring antibiotics by 55%.
BMJ editor Dr. Fiona Godlee, said "claims that oseltamivir reduces complications have been a key justification for promoting the drug's widespread use. Governments around the world have spent billions of pounds on a drug that the scientific community has found itself unable to judge."
There is evidence that oseltamivir has a modest effect in reducing some minor flu symptoms and contagiousness in otherwise healthy adults by about one day, but this is probably not the main reason most doctors are prescribing the drug for their patients. This less important benefit may well be offset by the risks of the drug.
and the mouse micronucleus test
, Tamiflu tested positive in the Syrian hamster embryo (SHE) cell transformation test.
residue substitutions (His274Tyr) in the neuraminidase
enzyme.
(WHO) reported 314 samples of the prevalent 2009 pandemic H1N1 flu
tested worldwide have shown resistance to oseltamivir.
A study published in the 2009 June issue of Nature Biotechnology
also emphasized the need for augmentation of oseltamivir stockpiles with additional antiviral drugs, including zanamivir (Relenza), based on an evaluation of the performance of these drugs in the scenario that the 2009 H1N1 neuraminidase (NA) were to acquire the oseltamivir-resistance mutation, which is currently widespread in seasonal H1N1 strains.
H3N2
influenza A virus isolates resistant to oseltamivir were found in 18% of a group of 50 Japanese children treated with oseltamivir. Several explanations were proposed by the authors of the studies for the higher-than-expected resistance rate detected. First, children typically have a longer infection period, giving a longer time for resistance to develop. Second, Kiso et al. claim to have used more rigorous detection techniques than previous studies.
. She was being treated with oseltamivir at time of detection. de Jong et al. (2005) describe resistance development in two more Vietnamese patients suffering from H5N1, and compare their cases with six others. They suggest the emergence of a resistant strain may be associated with a patient's clinical deterioration. They also note the recommended dosage of oseltamivir does not always completely suppress viral replication, a situation that could favor the emergence of resistant strains. Moscona (2005) gives a good overview of the resistance issue, and says that personal stockpiles of oseltamivir could lead to underdosage and thus the emergence of resistant strains of H5N1.
Resistance is of concern in the scenario of an influenza pandemic (Wong and Yuen 2005), and may be more likely to develop in avian influenza than seasonal influenza due to the potentially longer duration of infection by novel viruses. Kiso et al. suggest "a higher prevalence of resistant viruses should be expected" during a pandemic. Resistant strains have also appeared in the EU.
H5N1 has not yet been transmissible from person to person, and is acquired by people working with or near infected poultry.
for oseltamivir is held by Gilead Sciences and is valid at least until 2016. Gilead licensed the exclusive rights to Roche in 1996. The drug does not enjoy patent protection in Thailand, the Philippines, Indonesia and several other countries. Gilead is politically well connected: Donald Rumsfeld
served as chairman from 1997 until he became U.S. Secretary of Defense in 2001; former Secretary of State George Shultz and the wife of former California Governor Pete Wilson
serve on the board.
Oseltamivir was widely used during the H5N1 avian influenza epidemic
in Southeast Asia
in 2005. In response to the epidemic, various governments – including those of the United Kingdom
, Canada
, Israel
, United States
and Australia
– stockpiled quantities of oseltamivir in preparation for a possible pandemic
.
In late October 2005, Roche announced it was suspending shipments to pharmacies in the United States and Canada until the North American seasonal flu outbreak began, to address concerns about private stockpiling and to preserve supplies for seasonal influenza. Sales were suspended in Hong Kong as well, and on November 8, 2005, also in China. Roche said it would instead send all supplies to China's health ministry.
On November 9, 2005, Vietnam became the first country to be granted permission by Roche to produce a generic version of oseltamivir. The week before, Thai authorities said they would begin producing generic oseltamivir, claiming that Roche had not patented Tamiflu in Thailand. The first Thai generic oseltamivir was produced in February 2006 and was to have been available to the public in July 2006.
In November 2005, U.S. President George W. Bush
requested that Congress fund US$1 billion for the production and stockpile of oseltamivir, after Congress had already approved $1.8 billion for military use of the drug. Defense Secretary Rumsfeld recused himself from all government decisions regarding the drug.
In December 2005, Roche also signed a sublicense for complete oseltamivir production with China's Shanghai Pharmaceuticals, and by March 2006, a sublicense had also been granted to India's Hetero.
In late May 2006, the WHO asked Roche to be ready to ship an emergency stockpile of oseltamivir to Indonesia if needed. The alert was in response to suspected human-to-human transmission within a family, and was planned to last for two weeks.
In December 2008, the Indian drug company, Cipla
won its case in India's court system allowing it to manufacture a cheaper generic version of Tamiflu, called Antiflu. In May 2009, Cipla won approval from the WHO certifying that its drug Antiflu was as effective as Tamiflu, and Antiflu is included in the WHO list of prequalified medicinal products.
While current demand for seasonal influenza treatment and pandemic stockpiling are being met, it is unclear what the situation would be if a pandemic actually started. Doctors are now testing a doubling of the standard dose with the hope it would cut H5N1 influenza virus death rate. If this became the new standard, it would decrease the effective supply.
According to Roche, the major bottleneck in oseltamivir production is the availability of shikimic acid
, which cannot be synthesised economically and is only effectively isolated from Chinese star anise
, an ancient cooking spice; the herb is also used in traditional Chinese medicine
. Although most autotroph
ic organisms produce shikimic acid, the isolation yield is low. A shortage of star anise is one of the key reasons why there is a worldwide shortage of Tamiflu (as of 2005). Star anise is grown in four provinces in China and harvested between March and May. It is also produced in Lang Son province, Vietnam. The shikimic acid is extracted from the seeds in a ten-stage process. Thirteen grams of star anise make 1.3 grams of shikimic acid, which can be made into 10 oseltamivir 75 mg capsules. Ninety percent of the harvest is already used by Roche in making oseltamivir.
Some academic experts and other drug companies are disputing the difficulty of producing shikimic acid
by means other than star anise
extraction. An alternative method for production of the acid involves fermentation of genetically modified bacteria. Recently, biosynthetic pathways in Escherichia coli
have been enhanced to allow the organism to accumulate enough shikimic acid to be used commercially. Canadian generic drug company Apotex
is attempting to modify oseletamivir to use a synthetic alternative to shikimic acid. Other potential sources of shikimic acid include the sweetgum and ginkgo trees. Quinic acid
, derived from the bark of the cinchona
tree, is a potential alternative base material for the production of oseltamivir. In addition, aminoshikimic acid
, biosynthesized via fermentation of genetically modified bacteria (Guo and Frost), is a very promising alternative starting material for the production of oseltamivir.
The multistep synthesis above shows that although the major bottleneck for Roche may be the availability of shikimic acid, production of oseltamivir is very involved. Increasing production volume (by Roche or others) would require construction of extensive new facilities (which may not be amenable to scaleup and, even if identical on paper, may not necessarily produce acceptable yields), and even if current facilities could handle a larger feedstock quantity, there would be a delay in production as the material makes it down the pipeline (~6 months or so). Producing large amounts of Tamiflu not only takes months to complete, but is also hazardous. Some of the steps in the synthesis require careful handling and relatively mild reaction conditions, as they involve the use of potentially explosive azide chemistry. Roche has explored ways to speed up production (Chimia 2004, 58, 621). It has developed an azide-free allylamine route from the epoxide to Tamiflu. It has also crafted routes that do not rely on (–)-shikimic acid: a Diels-Alder-based one that uses furan and ethyl acrylate as starting materials, and another that relies on catalytic hydrogenation of an isophthalic acid
derivative followed by enzymatic desymmetrization. In addition, Frost and Guo at Michigan State University
have developed a microbial synthesis of aminoshikimic acid, which could reduce the need for azide chemistry if used as a starting material.
In the New England Journal of Medicine, Anne Moscona (2005) argues that the use of personal stockpiles of oseltamivir could result in the administration of low dosages, allowing for the development of drug-resistant virus strains. Many stockpilers will only have ten 75 mg pills (the current recommended dosage for oseltamivir), but this may be insufficient for the treatment of H5N1.
Another argument against individual stockpiling is that limited drugs should be kept for more strategic deployment, that is, to hard-hit areas, to people in critical roles (e.g., healthcare and government workers), to people vulnerable to seasonal flu, or to people who actually have come down with avian influenza. Ethical arguments are sometimes made as to whether affluent people or nations should have preferred access to antiviral medications. Illegal importation might divert the drug from poorer countries where the risk of avian influenza is actually higher. A counter argument is that it is difficult to justify prohibition of individual stockpiling, when some of the same arguments are pertinent to corporate stockpiling, which is both allowed and encouraged.
A third argument is that it would be difficult for home users to determine whether illegally imported Tamiflu is counterfeit. In December 2005, 53 packages of counterfeit Tamiflu tablets were intercepted by the US Customs Service in South San Francisco. The packages were labeled "Generic Tamiflu". Roche officials know of only one instance of counterfeit Tamiflu appearing outside of the United States: incorrectly labelled tablets found in Holland, which contained only vitamin C and lactose.
An argument in favor of individual stockpiling is that Roche is on the record as saying that without more orders, they may have to actually curtail production. Individual stockpiling could bring market forces to play, maintaining production capacity and allowing the total supply on hand to be higher in case demand again outstrips production in the future, for instance, during a sudden influenza outbreak.
infection. The drug may limit the ability of the virus to invade the crypt
cells of the small intestine
and decrease gastrointestinal bacteria
l colonization and toxin production.
The current production method features a number of reaction steps, two of which involve potentially hazardous azide
s. A reported azide-free Roche synthesis of the drug is summarized graphically below:
International Nonproprietary Name
An International Nonproprietary Name is the official nonproprietary or generic name given to a pharmaceutical substance, as designated by the World Health Organization...
(icon), an antiviral drug
Antiviral drug
Antiviral drugs are a class of medication used specifically for treating viral infections. Like antibiotics for bacteria, specific antivirals are used for specific viruses...
, slows the spread of influenza
Influenza
Influenza, commonly referred to as the flu, is an infectious disease caused by RNA viruses of the family Orthomyxoviridae , that affects birds and mammals...
(flu) virus between cells in the body by stopping the virus from chemically cutting ties
Viral neuraminidase
Viral neuraminidase is a type of neuraminidase found on the surface of influenza viruses that enables the virus to be released from the host cell...
with its host cell; median time to symptom alleviation is reduced by 0.5–1 day. The drug is sold under the trade name
Trade name
A trade name, also known as a trading name or a business name, is the name which a business trades under for commercial purposes, although its registered, legal name, used for contracts and other formal situations, may be another....
Tamiflu, and is taken orally in capsules or as a suspension. It has been used to treat and prevent influenza A virus and influenza B virus infection in over 50 million people since 1999.
Oseltamivir is a prodrug
Prodrug
A prodrug is a pharmacological substance administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and...
, a (relatively) inactive chemical which is converted into its active form by metabolic process after it is taken into the body. It was the first orally active neuraminidase inhibitor
Neuraminidase inhibitor
Neuraminidase inhibitors are a class of antiviral drugs targeted at the influenza virus, which work by blocking the function of the viral neuraminidase protein, thus preventing the virus from reproducing by budding from the host cell....
commercially developed. It was developed by C.U. Kim, W. Lew, and X. Chen of US-based Gilead Sciences
Gilead Sciences
Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes therapeutics. For many years since the company was founded, the company concentrated primarily on antiviral drugs to treat patients infected with HIV, hepatitis B or influenza. In 2006, Gilead acquired two...
, and is currently marketed by Hoffmann–La Roche (Roche). In Japan, it is marketed by Chugai Pharmaceutical Co.
Chugai Pharmaceutical Co.
Chugai Pharmaceutical Co., Ltd. is a subsidiary drug manufacturer operating in Japan controlled by Hoffmann–La Roche, which owns 52% of the company...
, which is more than 50% owned by Roche.
, the World Health Organization
World Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...
(WHO) reported 314 samples of the prevalent 2009 pandemic H1N1 flu
2009 flu pandemic
The 2009 flu pandemic was an influenza pandemic, and the second of the two pandemics involving H1N1 influenza virus , albeit in a new version...
tested worldwide have shown resistance to oseltamivir.
Mechanism of action
The prodrug oseltamivir is itself not virally effective; however, once in the liverLiver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
, it is converted by natural chemical processes, hydrolysed
Hydrolysis
Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...
hepatically to its active metabolite, the free carboxylate
Carboxylic acid
Carboxylic acids are organic acids characterized by the presence of at least one carboxyl group. The general formula of a carboxylic acid is R-COOH, where R is some monovalent functional group...
of oseltamivir (GS4071).
Oseltamivir is a neuraminidase inhibitor
Neuraminidase inhibitor
Neuraminidase inhibitors are a class of antiviral drugs targeted at the influenza virus, which work by blocking the function of the viral neuraminidase protein, thus preventing the virus from reproducing by budding from the host cell....
, serving as a competitive inhibitor towards sialic acid
Sialic acid
Sialic acid is a generic term for the N- or O-substituted derivatives of neuraminic acid, a monosaccharide with a nine-carbon backbone. It is also the name for the most common member of this group, N-acetylneuraminic acid...
, found on the surface proteins of normal host cells. By blocking the activity of the viral neuraminidase (NA) enzyme, oseltamivir prevents new viral particles from being released by infected cells.
Indications and dosage
Oseltamivir is marketed by Roche under the trade name Tamiflu, as capsules (containing oseltamivir phosphate 98.5 mg equivalent to oseltamivir 75 mg) and as a powder for oral suspension (oseltamivir phosphate equivalent to oseltamivir 12 mg/ml).Oseltamivir is indicated for the treatment and prevention of infections due to influenza A and B viruses.
Oseltamivir is approved for use in persons age one and over. There is also currently an FDA Emergency Use authorization temporarily allowing the use of Tamiflu in children less than one year old. The usual adult dosage for treatment of influenza is 75 mg twice daily for five days, beginning within two days of the appearance of symptoms, with decreased doses for children and patients with renal impairment. It may be given as a preventive measure either during a community outbreak or following close contact with an infected individual. Standard prophylactic dosage is 75 mg once daily for patients aged 13 and older, which has been shown to be safe and effective for up to six weeks. The importance of early treatment is that the NA protein inhibition is more effective within the first 48 hours. If the virus has replicated and infected many cells, the effectiveness of this medication will be severely diminished, especially over time.
The Centers for Disease Control and Prevention
Centers for Disease Control and Prevention
The Centers for Disease Control and Prevention are a United States federal agency under the Department of Health and Human Services headquartered in Druid Hills, unincorporated DeKalb County, Georgia, in Greater Atlanta...
(CDC) recommends physicians prioritize which patients to whom they prescribe oseltamivir: specifically, people hospitalized with more severe illness, children younger than two years old, adults over 65, pregnant women, people with certain chronic medical or immunosuppressive conditions and adults under 19 on long-term aspirin
Aspirin
Aspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer...
therapy. However, they also advise children and adults presenting with suspected flu who have symptoms of lower respiratory tract illness or clinical deterioration should also receive prompt empiric antiviral therapy, regardless of previous health or age.
The standard recommended dose incompletely suppresses viral replication in at least some patients with H5N1
H5N1
Influenza A virus subtype H5N1, also known as "bird flu", A or simply H5N1, is a subtype of the influenza A virus which can cause illness in humans and many other animal species...
avian influenza, increasing the risk of viral resistance and rendering therapy less effective. Accordingly, higher doses and longer durations of therapy have been suggested for treatment of patients with the H5N1 virus.
Clinical trials for an increased dosage began in May 2007. All avian influenza cases in Indonesia, Thailand, and Vietnam were inducted into the trial. The trial also included 100 cases of severe seasonal influenza from each of those countries and the United States. Half received the current standard dose, and half received a double dose, but for the standard length of time.
Coadministration with probenecid
Coadministration of oseltamivir with probenecidProbenecid
Probenecid is a uricosuric drug that increases uric acid excretion in the urine. It is primarily used in treating gout and hyperuricemia.Probenecid was developed as an alternative to caronamide...
has been suggested as a method to extend a limited supply of oseltamivir. Probenecid reduces renal excretion of the active metabolite of oseltamivir. One study showed that 500 mg of probenecid given every six hours doubled both the peak plasma concentration (Cmax) and the half life of oseltamivir, increasing overall systemic exposure (AUC) by 150 percent. Although the evidence for this interaction comes from a study by Roche, it was publicized only in October 2005 by a doctor who had reviewed the data. Probenecid was used in similar fashion during World War II
World War II
World War II, or the Second World War , was a global conflict lasting from 1939 to 1945, involving most of the world's nations—including all of the great powers—eventually forming two opposing military alliances: the Allies and the Axis...
to extend limited supplies of penicillin
Penicillin
Penicillin is a group of antibiotics derived from Penicillium fungi. They include penicillin G, procaine penicillin, benzathine penicillin, and penicillin V....
. It is still used to increase penicillin concentrations in serious infections.
Efficacy
On December 8, 2009, the Cochrane CollaborationCochrane Collaboration
The Cochrane Collaboration is a group of over 28,000 volunteers in more than 100 countries who review the effects of health care interventions tested in biomedical randomized controlled trials. A few more recent reviews have also studied the results of non-randomized, observational studies...
, which reviews medical evidence, in a review published in the British Medical Journal
British Medical Journal
BMJ is a partially open-access peer-reviewed medical journal. Originally called the British Medical Journal, the title was officially shortened to BMJ in 1988. The journal is published by the BMJ Group, a wholly owned subsidiary of the British Medical Association...
, announced it had reversed its previous findings that the antiviral drug Tamiflu can ward off pneumonia and other serious conditions linked to influenza. They reported an analysis of 20 studies showed Tamiflu offered mild benefits in terms of duration of symptoms for healthy adults if taken within 24 hours of onset of symptoms, but found no clear evidence it prevented lower respiratory tract infections or other complications of influenza. These findings relate only to its use in healthy adults with influenza, not in patients judged to be at high risk of complications. Tamiflu may still be a useful drug for reducing the duration of symptoms, although for this use it still has yet to be compared with NSAID
Non-steroidal anti-inflammatory drug
Nonsteroidal anti-inflammatory drugs, usually abbreviated to NSAIDs or NAIDs, but also referred to as nonsteroidal anti-inflammatory agents/analgesics or nonsteroidal Anti-inflammatory medicines , are drugs with analgesic and antipyretic effects and which have, in higher doses, anti-inflammatory...
s or paracetamol
Paracetamol
Paracetamol INN , or acetaminophen USAN , is a widely used over-the-counter analgesic and antipyretic . It is commonly used for the relief of headaches and other minor aches and pains and is a major ingredient in numerous cold and flu remedies...
.
Possible side effects
Adverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...
s (ADRs) associated with oseltamivir therapy (occurring in over 1% of clinical trial participants) include: nausea, vomiting, diarrhea, abdominal pain, and headache. Rare ADRs include: hepatitis
Hepatitis
Hepatitis is a medical condition defined by the inflammation of the liver and characterized by the presence of inflammatory cells in the tissue of the organ. The name is from the Greek hepar , the root being hepat- , meaning liver, and suffix -itis, meaning "inflammation"...
and elevated liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s, rash, allergic reactions including anaphylaxis
Anaphylaxis
Anaphylaxis is defined as "a serious allergic reaction that is rapid in onset and may cause death". It typically results in a number of symptoms including throat swelling, an itchy rash, and low blood pressure...
, and Stevens–Johnson syndrome.
Various other ADRs have been reported in postmarketing surveillance, including: toxic epidermal necrolysis
Toxic epidermal necrolysis
Toxic epidermal necrolysis is a rare, life-threatening dermatological condition that is usually induced by a reaction to medications...
, cardiac arrhythmia, seizure, confusion, aggravation of diabetes, and haemorrhagic colitis
Colitis
In medicine, colitis refers to an inflammation of the colon and is often used to describe an inflammation of the large intestine .Colitides may be acute and self-limited or chronic, i.e...
.
There are concerns that oseltamivir may cause dangerous psychological, neuropsychiatric side effects including self harm in some users. These dangerous side effects occur more commonly in children than in adults. This stems from cases in Japan, where the drug is most heavily prescribed, consuming 60% of the world's production. Concern has focused on teenagers, but problems have also been reported in children and adults.
In March 2007, Japan's Health Ministry warned that oseltamivir should not be given to those aged 10 to 19. The Ministry had previously decided, in May 2004, to change the literature accompanying oseltamivir to include neurological and psychological disorders as possible adverse effects, including impaired consciousness, abnormal behavior, and hallucination
Hallucination
A hallucination, in the broadest sense of the word, is a perception in the absence of a stimulus. In a stricter sense, hallucinations are defined as perceptions in a conscious and awake state in the absence of external stimuli which have qualities of real perception, in that they are vivid,...
s.
According to Japan's Health Ministry, between 2004 and March 2007, fifteen people aged 10 to 19 have been injured or killed by jumps or falls from buildings after taking oseltamivir, and one 17-year-old died after he jumped in front of a truck. A renewed investigation of the Japanese data was completed in April 2007. It found that 128 patients had been reported to behave abnormally after taking oseltamivir since 2001. Forty-three of them were under 10 years old, 57 patients were aged 10 to 19, and 28 patients were aged 20 or over. Eight people, including five teens and three adults, had died from these actions.
In October 2006, Shumpei Yokota, a professor of pediatrics at Yokohama City University, released the results of research involving around 2,800 children which found no difference in the behavior between those who took oseltamivir and those who did not. Chugai Pharmaceutical Co.
Chugai Pharmaceutical Co.
Chugai Pharmaceutical Co., Ltd. is a subsidiary drug manufacturer operating in Japan controlled by Hoffmann–La Roche, which owns 52% of the company...
(which produces oseltamivir in Japan) gave Yokota's department 10 million yen (about US$105,000) over five years.
To determine whether to lift the 2007 ban, a research team from the Japanese Health, Labour and Welfare Ministry studied 10,000 children under the age of 18 who had been diagnosed with influenza since 2006. The study was finalized in April 2009. Taking into account all degrees of abnormal behavior, including minor behavioral problems such as incoherent speech, the study found children who took oseltamivir were 54 percent more likely to exhibit abnormal behaviour than those who did not take the drug. When the team limited its analysis to children who had displayed serious abnormal behavior that led to injury or death, it found those who had taken oseltamivir were 25% more likely to behave unusually.
In November 2006, the United States Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) amended the warning label to include the possible side effects of delirium
Delirium
Delirium or acute confusional state is a common and severe neuropsychiatric syndrome with core features of acute onset and fluctuating course, attentional deficits and generalized severe disorganization of behavior...
, hallucinations, or other related behavior. This went further than the FDA's previous pronouncement, from a year before, that there was insufficient evidence to claim a causal link between oseltamivir use and the deaths of 12 Japanese children (only two were from neurological problems, although more have died since then). The change to a more cautionary stance was attributed to 103 new reports the FDA received of delirium, hallucinations and other unusual psychiatric behavior, mostly involving Japanese patients, received between August 29, 2005 and July 6, 2006. This was an increase from the 126 similar cases logged between the drug's approval in 1999 and August 2005.
Roche points out that oseltamivir has been used to treat over 50 million people since 1999, and states the influenza may itself cause psychological problems.
In March 2007, the European Medicines Agency said that the benefits of oseltamivir outweighed the costs, but that it would closely monitor reports from Japan.
In April 2007, South Korea issued a safety warning against prescribing oseltamivir to teenagers except in special cases.
A joint investigation by the British Medical Journal (BMJ) and British TV Channel 4 published in the BMJ on December 8, 2009 concluded that in otherwise healthy adults they "have no confidence in claims that oseltamivir reduces the risk of complications and hospital admission in people with influenza" and believe it should not be used in routine control of seasonal influenza. There was also concern about underreporting of side effects of the drug. In contrast, according to the BMJ, Roche has stated in media briefings that oseltamivir reduced hospital admissions by 61%; secondary complications (including bronchitis, pneumonia, and sinusitis) by 67% in otherwise healthy individuals and lower respiratory tract infections requiring antibiotics by 55%.
BMJ editor Dr. Fiona Godlee, said "claims that oseltamivir reduces complications have been a key justification for promoting the drug's widespread use. Governments around the world have spent billions of pounds on a drug that the scientific community has found itself unable to judge."
There is evidence that oseltamivir has a modest effect in reducing some minor flu symptoms and contagiousness in otherwise healthy adults by about one day, but this is probably not the main reason most doctors are prescribing the drug for their patients. This less important benefit may well be offset by the risks of the drug.
Mutagenesis, cell transformation, impairment of fertility, and carcinogenesis
Although found to be nonmutagenic in the Ames testAmes test
The Ames test is a biological assay to assess the mutagenic potential of chemical compounds. A positive test indicates that the chemical is mutagenic and therefore may act as a carcinogen, since cancer is often linked to mutation. However, a number of false-positives and false-negatives are known...
and the mouse micronucleus test
Micronucleus test
A micronucleus test is a test used in toxicological screening for potential genotoxic compounds. There are two major versions of this test, one in vivo and the other In vitro. The in vivo test normally uses mouse bone marrow or mouse peripheral blood. Micronuclei were first used to quantify...
, Tamiflu tested positive in the Syrian hamster embryo (SHE) cell transformation test.
Resistance
Mutations conferring resistance are single amino acidAmino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
residue substitutions (His274Tyr) in the neuraminidase
Neuraminidase
Neuraminidase enzymes are glycoside hydrolase enzymes that cleave the glycosidic linkages of neuraminic acids. Neuraminidase enzymes are a large family, found in a range of organisms. The most commonly known neuraminidase is the viral neuraminidase, a drug target for the prevention of the spread...
enzyme.
2009 pandemic H1N1 flu
, the World Health OrganizationWorld Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...
(WHO) reported 314 samples of the prevalent 2009 pandemic H1N1 flu
2009 flu pandemic
The 2009 flu pandemic was an influenza pandemic, and the second of the two pandemics involving H1N1 influenza virus , albeit in a new version...
tested worldwide have shown resistance to oseltamivir.
A study published in the 2009 June issue of Nature Biotechnology
Nature Biotechnology
Nature Biotechnology is an academic journal covering the science and business of biotechnology.Nature Biotechnology is a continuation of Bio/Technology , which was founded in 1983 and renamed in 1996. It is published monthly by the Nature Publishing Group, a division of Macmillan Publishers Ltd...
also emphasized the need for augmentation of oseltamivir stockpiles with additional antiviral drugs, including zanamivir (Relenza), based on an evaluation of the performance of these drugs in the scenario that the 2009 H1N1 neuraminidase (NA) were to acquire the oseltamivir-resistance mutation, which is currently widespread in seasonal H1N1 strains.
Seasonal H1N1
According to the CDC, oseltamivir is not very effective in the 2008 seasonal H1N1 virus anymore due to acquired resistance in 99.6% of all 2008 seasonal H1N1 strains, up from 12% in 2007-2008 flu season.H3N2
MutantMutant
In biology and especially genetics, a mutant is an individual, organism, or new genetic character, arising or resulting from an instance of mutation, which is a base-pair sequence change within the DNA of a gene or chromosome of an organism resulting in the creation of a new character or trait not...
H3N2
H3N2
Influenza A virus subtype H3N2 is a subtype of viruses that cause influenza . H3N2 Viruses can infect birds and mammals. In birds, humans, and pigs, the virus has mutated into many strains...
influenza A virus isolates resistant to oseltamivir were found in 18% of a group of 50 Japanese children treated with oseltamivir. Several explanations were proposed by the authors of the studies for the higher-than-expected resistance rate detected. First, children typically have a longer infection period, giving a longer time for resistance to develop. Second, Kiso et al. claim to have used more rigorous detection techniques than previous studies.
Influenza B
In 2007, Japanese investigators detected neuraminidase-resistant influenza B virus strains in individuals who had not been treated with these drugs. The prevalence was 1.7%. According to the CDC, as of October 3, 2009 no influenza B strains tested have shown any resistance to oseltamivir.H5N1 avian influenza
High-level resistance has been detected in one girl suffering from H5N1 avian influenza in VietnamVietnam
Vietnam – sometimes spelled Viet Nam , officially the Socialist Republic of Vietnam – is the easternmost country on the Indochina Peninsula in Southeast Asia. It is bordered by China to the north, Laos to the northwest, Cambodia to the southwest, and the South China Sea –...
. She was being treated with oseltamivir at time of detection. de Jong et al. (2005) describe resistance development in two more Vietnamese patients suffering from H5N1, and compare their cases with six others. They suggest the emergence of a resistant strain may be associated with a patient's clinical deterioration. They also note the recommended dosage of oseltamivir does not always completely suppress viral replication, a situation that could favor the emergence of resistant strains. Moscona (2005) gives a good overview of the resistance issue, and says that personal stockpiles of oseltamivir could lead to underdosage and thus the emergence of resistant strains of H5N1.
Resistance is of concern in the scenario of an influenza pandemic (Wong and Yuen 2005), and may be more likely to develop in avian influenza than seasonal influenza due to the potentially longer duration of infection by novel viruses. Kiso et al. suggest "a higher prevalence of resistant viruses should be expected" during a pandemic. Resistant strains have also appeared in the EU.
H5N1 has not yet been transmissible from person to person, and is acquired by people working with or near infected poultry.
Commercial issues
The patentPatent
A patent is a form of intellectual property. It consists of a set of exclusive rights granted by a sovereign state to an inventor or their assignee for a limited period of time in exchange for the public disclosure of an invention....
for oseltamivir is held by Gilead Sciences and is valid at least until 2016. Gilead licensed the exclusive rights to Roche in 1996. The drug does not enjoy patent protection in Thailand, the Philippines, Indonesia and several other countries. Gilead is politically well connected: Donald Rumsfeld
Donald Rumsfeld
Donald Henry Rumsfeld is an American politician and businessman. Rumsfeld served as the 13th Secretary of Defense from 1975 to 1977 under President Gerald Ford, and as the 21st Secretary of Defense from 2001 to 2006 under President George W. Bush. He is both the youngest and the oldest person to...
served as chairman from 1997 until he became U.S. Secretary of Defense in 2001; former Secretary of State George Shultz and the wife of former California Governor Pete Wilson
Pete Wilson
Peter Barton "Pete" Wilson is an American politician from California. Wilson, a Republican, served as the 36th Governor of California , the culmination of more than three decades in the public arena that included eight years as a United States Senator , eleven years as Mayor of San Diego and...
serve on the board.
Oseltamivir was widely used during the H5N1 avian influenza epidemic
Epidemic
In epidemiology, an epidemic , occurs when new cases of a certain disease, in a given human population, and during a given period, substantially exceed what is expected based on recent experience...
in Southeast Asia
Southeast Asia
Southeast Asia, South-East Asia, South East Asia or Southeastern Asia is a subregion of Asia, consisting of the countries that are geographically south of China, east of India, west of New Guinea and north of Australia. The region lies on the intersection of geological plates, with heavy seismic...
in 2005. In response to the epidemic, various governments – including those of the United Kingdom
United Kingdom
The United Kingdom of Great Britain and Northern IrelandIn the United Kingdom and Dependencies, other languages have been officially recognised as legitimate autochthonous languages under the European Charter for Regional or Minority Languages...
, Canada
Canada
Canada is a North American country consisting of ten provinces and three territories. Located in the northern part of the continent, it extends from the Atlantic Ocean in the east to the Pacific Ocean in the west, and northward into the Arctic Ocean...
, Israel
Israel
The State of Israel is a parliamentary republic located in the Middle East, along the eastern shore of the Mediterranean Sea...
, United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
and Australia
Australia
Australia , officially the Commonwealth of Australia, is a country in the Southern Hemisphere comprising the mainland of the Australian continent, the island of Tasmania, and numerous smaller islands in the Indian and Pacific Oceans. It is the world's sixth-largest country by total area...
– stockpiled quantities of oseltamivir in preparation for a possible pandemic
Pandemic
A pandemic is an epidemic of infectious disease that is spreading through human populations across a large region; for instance multiple continents, or even worldwide. A widespread endemic disease that is stable in terms of how many people are getting sick from it is not a pandemic...
.
In late October 2005, Roche announced it was suspending shipments to pharmacies in the United States and Canada until the North American seasonal flu outbreak began, to address concerns about private stockpiling and to preserve supplies for seasonal influenza. Sales were suspended in Hong Kong as well, and on November 8, 2005, also in China. Roche said it would instead send all supplies to China's health ministry.
On November 9, 2005, Vietnam became the first country to be granted permission by Roche to produce a generic version of oseltamivir. The week before, Thai authorities said they would begin producing generic oseltamivir, claiming that Roche had not patented Tamiflu in Thailand. The first Thai generic oseltamivir was produced in February 2006 and was to have been available to the public in July 2006.
In November 2005, U.S. President George W. Bush
George W. Bush
George Walker Bush is an American politician who served as the 43rd President of the United States, from 2001 to 2009. Before that, he was the 46th Governor of Texas, having served from 1995 to 2000....
requested that Congress fund US$1 billion for the production and stockpile of oseltamivir, after Congress had already approved $1.8 billion for military use of the drug. Defense Secretary Rumsfeld recused himself from all government decisions regarding the drug.
In December 2005, Roche also signed a sublicense for complete oseltamivir production with China's Shanghai Pharmaceuticals, and by March 2006, a sublicense had also been granted to India's Hetero.
In late May 2006, the WHO asked Roche to be ready to ship an emergency stockpile of oseltamivir to Indonesia if needed. The alert was in response to suspected human-to-human transmission within a family, and was planned to last for two weeks.
In December 2008, the Indian drug company, Cipla
Cipla
Cipla Limited is a prominent Indian pharmaceutical company, best-known outside its home country for manufacturing low-cost anti-AIDS drugs for HIV-positive patients in developing countries...
won its case in India's court system allowing it to manufacture a cheaper generic version of Tamiflu, called Antiflu. In May 2009, Cipla won approval from the WHO certifying that its drug Antiflu was as effective as Tamiflu, and Antiflu is included in the WHO list of prequalified medicinal products.
Production shortage/shikimic acid
In early 2005, Roche announced a production shortage. (See Pandemic Fears, above). In 2006, however, Roche said production was about to reach 400-million treatment courses annually, that "capacity was well in excess of total government orders placed to date," and "the supply shortage no longer exists." Total government orders between 2005 and 2007 were estimated to be around 200 million treatment doses. In fact, Roche CEO William Burns said a shortage of orders could cause Roche to reduce production in the future. Roche attributes production increases in part to its agreements with 15 external contractors in 9 countries.While current demand for seasonal influenza treatment and pandemic stockpiling are being met, it is unclear what the situation would be if a pandemic actually started. Doctors are now testing a doubling of the standard dose with the hope it would cut H5N1 influenza virus death rate. If this became the new standard, it would decrease the effective supply.
According to Roche, the major bottleneck in oseltamivir production is the availability of shikimic acid
Shikimic acid
Shikimic acid, more commonly known as its anionic form shikimate, is an important biochemical metabolite in plants and microorganisms. Its name comes from the Japanese flower shikimi , from which it was first isolated....
, which cannot be synthesised economically and is only effectively isolated from Chinese star anise
Star anise
Illicium verum, commonly called Star anise, star aniseed, or Chinese star anise, is a spice that closely resembles anise in flavor, obtained from the star-shaped pericarp of Illicium verum, a small native evergreen tree of northeast Vietnam and southwest China...
, an ancient cooking spice; the herb is also used in traditional Chinese medicine
Traditional Chinese medicine
Traditional Chinese Medicine refers to a broad range of medicine practices sharing common theoretical concepts which have been developed in China and are based on a tradition of more than 2,000 years, including various forms of herbal medicine, acupuncture, massage , exercise , and dietary therapy...
. Although most autotroph
Autotroph
An autotroph, or producer, is an organism that produces complex organic compounds from simple inorganic molecules using energy from light or inorganic chemical reactions . They are the producers in a food chain, such as plants on land or algae in water...
ic organisms produce shikimic acid, the isolation yield is low. A shortage of star anise is one of the key reasons why there is a worldwide shortage of Tamiflu (as of 2005). Star anise is grown in four provinces in China and harvested between March and May. It is also produced in Lang Son province, Vietnam. The shikimic acid is extracted from the seeds in a ten-stage process. Thirteen grams of star anise make 1.3 grams of shikimic acid, which can be made into 10 oseltamivir 75 mg capsules. Ninety percent of the harvest is already used by Roche in making oseltamivir.
Some academic experts and other drug companies are disputing the difficulty of producing shikimic acid
Shikimic acid
Shikimic acid, more commonly known as its anionic form shikimate, is an important biochemical metabolite in plants and microorganisms. Its name comes from the Japanese flower shikimi , from which it was first isolated....
by means other than star anise
Star anise
Illicium verum, commonly called Star anise, star aniseed, or Chinese star anise, is a spice that closely resembles anise in flavor, obtained from the star-shaped pericarp of Illicium verum, a small native evergreen tree of northeast Vietnam and southwest China...
extraction. An alternative method for production of the acid involves fermentation of genetically modified bacteria. Recently, biosynthetic pathways in Escherichia coli
Escherichia coli
Escherichia coli is a Gram-negative, rod-shaped bacterium that is commonly found in the lower intestine of warm-blooded organisms . Most E. coli strains are harmless, but some serotypes can cause serious food poisoning in humans, and are occasionally responsible for product recalls...
have been enhanced to allow the organism to accumulate enough shikimic acid to be used commercially. Canadian generic drug company Apotex
Apotex
Apotex is a Canadian pharmaceutical corporation. Founded in 1974, the company is the largest producer of generic drugs in Canada, with sales exceeding one billion dollars a year...
is attempting to modify oseletamivir to use a synthetic alternative to shikimic acid. Other potential sources of shikimic acid include the sweetgum and ginkgo trees. Quinic acid
Quinic acid
Quinic acid is a cyclitol, a cyclic polyol. It is a crystalline acid obtained from cinchona bark, coffee beans, and other plant products and made synthetically by hydrolysis of chlorogenic acid. Quinic acid is also implicated in the perceived acidity of coffee...
, derived from the bark of the cinchona
Cinchona
Cinchona or Quina is a genus of about 38 species in the family Rubiaceae, native to tropical South America. They are large shrubs or small trees growing 5–15 metres in height with evergreen foliage. The leaves are opposite, rounded to lanceolate and 10–40 cm long. The flowers are white, pink...
tree, is a potential alternative base material for the production of oseltamivir. In addition, aminoshikimic acid
Aminoshikimic acid
Aminoshikimic acid is a synthetic crystalline carboxylic acid. It is characterized by multiple stereogenic centers and functional groups arrayed around a six-membered carbocyclic ring...
, biosynthesized via fermentation of genetically modified bacteria (Guo and Frost), is a very promising alternative starting material for the production of oseltamivir.
The multistep synthesis above shows that although the major bottleneck for Roche may be the availability of shikimic acid, production of oseltamivir is very involved. Increasing production volume (by Roche or others) would require construction of extensive new facilities (which may not be amenable to scaleup and, even if identical on paper, may not necessarily produce acceptable yields), and even if current facilities could handle a larger feedstock quantity, there would be a delay in production as the material makes it down the pipeline (~6 months or so). Producing large amounts of Tamiflu not only takes months to complete, but is also hazardous. Some of the steps in the synthesis require careful handling and relatively mild reaction conditions, as they involve the use of potentially explosive azide chemistry. Roche has explored ways to speed up production (Chimia 2004, 58, 621). It has developed an azide-free allylamine route from the epoxide to Tamiflu. It has also crafted routes that do not rely on (–)-shikimic acid: a Diels-Alder-based one that uses furan and ethyl acrylate as starting materials, and another that relies on catalytic hydrogenation of an isophthalic acid
Isophthalic acid
Isophthalic acid is an organic compound with the formula C6H42. This colourless solid is an isomer of phthalic acid and terephthalic acid. These aromatic dicarboxylic acids are used as precursors to commercially important polymers, e.g. the fire-resistant material Nomex...
derivative followed by enzymatic desymmetrization. In addition, Frost and Guo at Michigan State University
Michigan State University
Michigan State University is a public research university in East Lansing, Michigan, USA. Founded in 1855, it was the pioneer land-grant institution and served as a model for future land-grant colleges in the United States under the 1862 Morrill Act.MSU pioneered the studies of packaging,...
have developed a microbial synthesis of aminoshikimic acid, which could reduce the need for azide chemistry if used as a starting material.
Personal stockpiling
A short supply of oseltamivir prompted some individuals to stockpile the drug. Several American states issued advisories strongly discouraging this practice. Production has since caught up with current demand (see above).In the New England Journal of Medicine, Anne Moscona (2005) argues that the use of personal stockpiles of oseltamivir could result in the administration of low dosages, allowing for the development of drug-resistant virus strains. Many stockpilers will only have ten 75 mg pills (the current recommended dosage for oseltamivir), but this may be insufficient for the treatment of H5N1.
Another argument against individual stockpiling is that limited drugs should be kept for more strategic deployment, that is, to hard-hit areas, to people in critical roles (e.g., healthcare and government workers), to people vulnerable to seasonal flu, or to people who actually have come down with avian influenza. Ethical arguments are sometimes made as to whether affluent people or nations should have preferred access to antiviral medications. Illegal importation might divert the drug from poorer countries where the risk of avian influenza is actually higher. A counter argument is that it is difficult to justify prohibition of individual stockpiling, when some of the same arguments are pertinent to corporate stockpiling, which is both allowed and encouraged.
A third argument is that it would be difficult for home users to determine whether illegally imported Tamiflu is counterfeit. In December 2005, 53 packages of counterfeit Tamiflu tablets were intercepted by the US Customs Service in South San Francisco. The packages were labeled "Generic Tamiflu". Roche officials know of only one instance of counterfeit Tamiflu appearing outside of the United States: incorrectly labelled tablets found in Holland, which contained only vitamin C and lactose.
An argument in favor of individual stockpiling is that Roche is on the record as saying that without more orders, they may have to actually curtail production. Individual stockpiling could bring market forces to play, maintaining production capacity and allowing the total supply on hand to be higher in case demand again outstrips production in the future, for instance, during a sudden influenza outbreak.
Veterinary use
There have been anecdotal reports of oseltamivir reducing disease severity and hospitalization time in canine parvovirusCanine parvovirus
Canine parvovirus type 2 is a contagious virus mainly affecting dogs. The disease is highly contagious and is spread from dog to dog by direct or indirect contact with their feces. It can be especially severe in puppies that are not protected by maternal antibodies or vaccination. It has two...
infection. The drug may limit the ability of the virus to invade the crypt
Crypt (anatomy)
Crypts are anatomical structures that are narrow but deep invaginations into a larger structure.One common type of anatomical crypt is the Crypts of Lieberkühn. However, it is not the only type: some types of tonsils also have crypts...
cells of the small intestine
Small intestine
The small intestine is the part of the gastrointestinal tract following the stomach and followed by the large intestine, and is where much of the digestion and absorption of food takes place. In invertebrates such as worms, the terms "gastrointestinal tract" and "large intestine" are often used to...
and decrease gastrointestinal bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
l colonization and toxin production.
Chemical synthesis
Aqueous solubility of oseltamivir in form of phosphate salt is 588 mg/ml at 25°C.The current production method features a number of reaction steps, two of which involve potentially hazardous azide
Azide
Azide is the anion with the formula N3−. It is the conjugate base of hydrazoic acid. N3− is a linear anion that is isoelectronic with CO2 and N2O. Per valence bond theory, azide can be described by several resonance structures, an important one being N−=N+=N−...
s. A reported azide-free Roche synthesis of the drug is summarized graphically below:
See also
- AmantadineAmantadineAmantadine is the organic compound known formally as 1-adamantylamine or 1-aminoadamantane. The molecule consists of adamantane backbone that has an amino group substituted at one of the four methyne positions. This pharmaceutical is sold under the name Symmetrel for use both as an antiviral and an...
and rimantadineRimantadineRimantadine is an orally administered antiviral drug used to treat, and in rare cases prevent, influenzavirus A infection. When taken within one to two days of developing symptoms, rimantadine can shorten the duration and moderate the severity of influenza. Both rimantadine and the similar drug...
- M2M2 proteinThe M2 protein is a proton-selective ion channel protein, integral in the viral envelope of the influenza A virus. The channel itself is a homotetramer , where the units are helices stabilized by two disulfide bonds...
inhibitors, other drugs used for influenza treatment - Avian influenza
- H5N1H5N1Influenza A virus subtype H5N1, also known as "bird flu", A or simply H5N1, is a subtype of the influenza A virus which can cause illness in humans and many other animal species...
- InfluenzaInfluenzaInfluenza, commonly referred to as the flu, is an infectious disease caused by RNA viruses of the family Orthomyxoviridae , that affects birds and mammals...
- Relenza / Zanamivir - another neuraminidase inhibitorNeuraminidase inhibitorNeuraminidase inhibitors are a class of antiviral drugs targeted at the influenza virus, which work by blocking the function of the viral neuraminidase protein, thus preventing the virus from reproducing by budding from the host cell....
Further reading
- Pollack, Andrew. Is Bird Flu Drug Really So Vexing? Debating the Difficulty of Tamiflu [News article]. The New York Times (Accessed on November 5, 2005 at http://www.nytimes.com/2005/11/05/business/05tamiflu.html)
External links
- New: Neuraminidase inhibitors have modest effectiveness
- www.tamiflu.com – Roche's page on Tamiflu (oseltamivir)
- MedlinePlus Drug Information: oseltamivir (systemic) –Last Revised - 05/01/2009 Advice for the Patient
- Pharmasquare – Tamiflu Mode of Action – Flash animation showing the mode of action of oseltamivir
- FDA information page on oseltamivir
- Flu Drugs FAQ – U.S. National Institute of Allergy and Infectious Diseases
- Reto U. Schneider: The race to develop GS4104 - A comprehensive feature story about the development of Tamiflu published in January 2004 in NZZ-Folio, the magazine of the daily Neue Zürcher Zeitung in Switzerland (translated from German).
- Journal Response – Oseltamivir – abstracts of recent oseltamivir research
- * TREATMENT OF PARVOVIRUS & KENNEL COUGH USING TAMIFLU