Oseltamivir

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Oseltamivir
Systematic (IUPAC) name
ethyl (3R,4R,5S)-5-amino-4-acetamido-3-(pentan-3-yloxy)-cyclohex-1-ene-1-carboxylate
Clinical data
Trade namesTamiflu
AHFS/Drugs.commonograph
MedlinePlusa699040
Licence dataUS Daily Med:link
Pregnancy cat.B1 (AU) C (US)
Legal statusPrescription Only (S4) (AU) POM (UK) -only (US)
Routesoral
Pharmacokinetic data
Bioavailability75%
MetabolismHepatic, to GS4071
Half-life6–10 hours
ExcretionRenal (GS4071)
Identifiers
CAS number196618-13-0 N
ATC codeJ05AH02
PubChemCID 65028
DrugBankDB00198
ChemSpider58540 YesY
UNII20O93L6F9H YesY
KEGGD08306 YesY
ChEBICHEBI:7798 YesY
ChEMBLCHEMBL1229 YesY
Chemical data
FormulaC16H28N2O8P 
Mol. mass312.4 g/mol
 N (what is this?)  (verify)
 
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Oseltamivir
Systematic (IUPAC) name
ethyl (3R,4R,5S)-5-amino-4-acetamido-3-(pentan-3-yloxy)-cyclohex-1-ene-1-carboxylate
Clinical data
Trade namesTamiflu
AHFS/Drugs.commonograph
MedlinePlusa699040
Licence dataUS Daily Med:link
Pregnancy cat.B1 (AU) C (US)
Legal statusPrescription Only (S4) (AU) POM (UK) -only (US)
Routesoral
Pharmacokinetic data
Bioavailability75%
MetabolismHepatic, to GS4071
Half-life6–10 hours
ExcretionRenal (GS4071)
Identifiers
CAS number196618-13-0 N
ATC codeJ05AH02
PubChemCID 65028
DrugBankDB00198
ChemSpider58540 YesY
UNII20O93L6F9H YesY
KEGGD08306 YesY
ChEBICHEBI:7798 YesY
ChEMBLCHEMBL1229 YesY
Chemical data
FormulaC16H28N2O8P 
Mol. mass312.4 g/mol
 N (what is this?)  (verify)

Oseltamivir INN /ɒsəlˈtæmɨvɪər/, marketed under the trade name Tamiflu, is an antiviral licensed to prevent or slow the spread of influenza A and influenza B (flu) virus between cells in the body by stopping the virus from chemically cutting ties with its host cell.[1] The drug is taken orally in capsules or as a suspension. 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.[citation needed] It was developed by C.U. Kim, W. Lew, and X. Chen of US-based Gilead Sciences,[2] and is marketed by Genentech.[3]

Oseltamivir's benefits in those who are otherwise healthy do not appear to outweigh its risks.[4] No benefit has been found in those with other health problems.[4][5] Prior to 2013, oseltamivir's effectiveness was debated as its manufacturer, Roche, originally refused to release the data from all of its trials for independent analysis (all data was not available to the official bodies that decided to licence/approve it).[6] Together, these published studies suggest that oseltamivir reduces the duration of symptoms by 0.5–1 day.[1] It is unclear whether this medication affects transmission of influenza in adults.[7] It does not appear to change the rate of complications from influenza, such as the risk of hospitalization or pneumonia.[5] However, it can increase rates of vomiting.[8]

As of December 15, 2010 (2010-12-15), the World Health Organization (WHO) reported 314 samples of the prevalent 2009 pandemic H1N1 flu tested worldwide have shown resistance to oseltamivir.[9] However, the predominant strains of both influenza A and influenza B active during the 2012-2013 flu season in the US are sensitive to oseltamivir.[10]

Medical use[edit]

When used for treatment or prevention in those that are otherwise healthy, it does not appear to have benefits that outweigh the risks.[4]

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.[11] Accordingly, higher doses and longer durations of therapy have been suggested for treatment of patients with the H5N1 virus.[11][12]

There is low to moderate evidence that it decreases the risk of getting influenza by 1% to 12% in those exposed.[4] It is unclear whether it affects the risk of needing to be hospitalized or the risk of death.[4] Oseltamivir is indicated for the treatment and prevention of infections due to influenza A and B viruses.[13] The predominant strains of both influenza A and influenza B active during the 2012-2013 flu season in the US are sensitive to oseltamivir.[10]

Efficacy[edit]

A 2012 Cochrane review maintains that significant parts of the clinical trials still remains unavailable for public scrutiny, and that the available evidence is not sufficient to conclude that oseltamivir decreases hospitalizations from influenza-like illnesses.[6] As of October 2012, 60% of Roche's clinical data concerning oseltamivir remains unpublished.[14]

It may still be a useful drug for reducing the duration of symptoms, although for this use it still has yet to be compared with NSAIDs or paracetamol.[15]

Roche commissioned an independent reanalysis of its data in 2011. One of the authors had received income from an organization sponsored by Roche previously but they were not funded by Roche for this analysis.[16] They concluded that early oseltamivir use reduced the number of lower respiratory tract infection treated with antibiotics from 9.3% to 5.9% in hitherto healthy adults and children.[16] No benefit occurred in those without an infection with influenza.[16]

Adverse effects[edit]

A package of capsules

Common adverse drug reactions (ADRs) associated with oseltamivir therapy (occurring in over 1 percent of clinical trial participants) include: nausea, vomiting, diarrhea, abdominal pain, and headache. Rare ADRs include: hepatitis and elevated liver enzymes, rash, allergic reactions including anaphylaxis, and Stevens–Johnson syndrome.[17][18]

Various other ADRs have been reported in postmarketing surveillance, including: toxic epidermal necrolysis, cardiac arrhythmia, seizure, confusion, aggravation of diabetes, and haemorrhagic colitis.[17]

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.[19] This stems from cases in Japan, where the drug is most heavily prescribed, consuming 60 percent of the world's production.[20]

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 hallucinations.[20]

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.[21] 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.[22][21][23]

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 that took oseltamivir and those that did not. Chugai Pharmaceutical Co. (which produces oseltamivir in Japan[citation needed]) gave Yokota's department 10 million yen (about US$105,000) over five years.[24]

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 that took oseltamivir were 54 percent more likely to exhibit abnormal behaviour than those that did not take the drug. When the team limited its analysis to children that had displayed serious abnormal behavior that led to injury or death, it found those that had taken oseltamivir were 25 percent more likely to behave unusually.[25]

In November 2006, the U.S. Food and Drug Administration (FDA) amended the warning label to include the possible side-effects of delirium, hallucinations, or other related behavior.[26] 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).[27] 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.[28]

Roche points out[when?] that oseltamivir has been used to treat over 50 million people since 1999, and states the influenza may itself cause psychological problems.[citation needed]

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.[citation needed]

In April 2007, South Korea issued a safety warning against prescribing oseltamivir to teenagers except in special cases.[29]

A joint investigation by the British Medical Journal (BMJ) and British TV Channel 4 published in the BMJ on December 8, 2009,[30] 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 percent; secondary complications (including bronchitis, pneumonia, and sinusitis) by 67 percent in otherwise-healthy individuals and lower respiratory tract infections requiring antibiotics by 55 percent.[citation needed]

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."[31]

Mutagenesis[edit]

Although found to be nonmutagenic in the Ames test and the mouse micronucleus test, oseltamivir tested positive in the Syrian hamster embryo (SHE) cell transformation test.[32][33]

Resistance[edit]

The vast majority of mutations conferring resistance are single amino acid residue substitutions (His274Tyr in N1) in the neuraminidase enzyme.[12]

2009 pandemic H1N1 flu[edit]

As of December 15, 2010 (2010-12-15), the World Health Organization (WHO) reported 314 samples of the prevalent 2009 pandemic H1N1 flu tested worldwide have shown resistance to oseltamivir.[9]

A study published in the June 2009 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.[34]

Seasonal flu[edit]

Resistance to Oseltamivir was widespread in seasonal flu from 2007-2009. In the 2007-2008 flu season, the US CDC found 10.9% of H1N1 samples (n=1,020) to be resistant.[35] In the 2008-2009 season, the proportion of resistant H1N1 increased to 99.4%. Other seasonal strains (H3N2, B) showed no resistance.[36] All Oseltamivir-resistant strains maintained sensitivity to zanamivir.

Resistance to Oseltamivir has been low in seasonal flu from 2009-2012. In the 2010-2011 flu season, the US CDC reported maintained Oseltamivir sensitivity in 99.1% of H1N1 (n=4,229), 99.8% of H3N2 (n=806), and 100% of Influenza B (n=723) samples tested.[37] As of January 2012, the US and European CDCs were reporting sensitivity to Oseltamivir for all (n=103) seasonal flu samples tested since October 2011.[38][39]

H3N2[edit]

Mutant H3N2 influenza A virus isolates resistant to oseltamivir were found in 18 percent of a group of 50 Japanese children treated with oseltamivir in 2002-2003.[40] 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.[40] Inadequate dosage may also have been an issue.[12]

Influenza B[edit]

In 2007, Japanese investigators detected neuraminidase-resistant influenza B virus strains in individuals having not been treated with these drugs. The prevalence was 1.7 percent.[41] According to the CDC, as of October 3, 2009 (2009-10-03) no influenza B strains tested have shown any resistance to oseltamivir.

H5N1 avian influenza[edit]

High-level resistance has been detected in one girl suffering from H5N1 avian influenza in Vietnam. She was being treated with oseltamivir at time of detection.[42][43] 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 that 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.[44]

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.[40] Resistant strains have also appeared in the EU.[45][46]

Mechanism of action[edit]

The prodrug oseltamivir is itself not virally effective; however, once in the liver it is hydrolysed to its active metabolite - the free carboxylate of oseltamivir (GS4071).[17]

Oseltamivir is a neuraminidase inhibitor, serving as a competitive inhibitor of the activity of the viral neuraminidase (NA) enzyme upon sialic acid, found on glycoproteins on the surface of normal host cells. By blocking the activity of the enzyme, oseltamivir prevents new viral particles from being released by infected cells.[17]

Commercial issues[edit]

The patent 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.[47] 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.[48]

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.[citation needed]

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.[49] 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.[50]

On November 9, 2005, Vietnam became the first country to be granted permission by Roche to produce a generic version of oseltamivir.[51] The week before, Thai authorities said they would begin producing generic oseltamivir, claiming that Roche had not patented Tamiflu in Thailand.[52] The first Thai generic oseltamivir was produced in February 2006, and was to have been available to the public in July 2006.[citation needed]

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.[53]

In December 2005, Roche 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.[54][55]

In 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.[56]

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.[57]

Marketing display used at festivals features a person living in a hermetically sealed environment

Production shortage/shikimic acid[edit]

In early 2005, Roche announced a production shortage. 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.[58][59][60]

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.[61] 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 effectively isolated only from Chinese star anise, an ancient cooking spice; the herb is also used in traditional Chinese medicine. Although most autotrophic organisms produce shikimic acid, the isolation yield is low. A shortage of star anise is one of the key reasons why there was a worldwide shortage of Tamiflu in 2005. Star anise is grown in four provinces in China and harvested between March and May. It is also produced in Lạng Sơn 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.

Some academic experts[who?] 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.[62][63][64] Canadian generic drug company Apotex is attempting[when?] to modify oseltamivir 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,[65] 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.[66] 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.[67]

Personal stockpiling[edit]

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).[citation needed]

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.[44] Many stockpilers will have pills of only ten 75 mg (the current[when?] recommended dosage for oseltamivir), but this may be insufficient for the treatment of H5N1.[11]

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 having 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.[58]

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 the appearance of counterfeit Tamiflu outside of the United States: incorrectly labeled tablets found in Holland, which contained only vitamin C and lactose.[68]

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.[59] 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[edit]

There have been reports of oseltamivir's reducing disease severity and hospitalization time in canine parvovirus infection.[69] The drug may limit the ability of the virus to invade the crypt cells of the small intestine and decrease gastrointestinal bacterial colonization and toxin production.[70]

Chemical synthesis[edit]

Aqueous solubility of oseltamivir in form of phosphate salt is 588 mg/ml at 25 °C (77 °F).[71]

The current[when?] production method features a number of reaction steps, two of which involving potentially hazardous azides. A reported azide-free Roche synthesis of the drug is summarized graphically below[72]

Synthesis of Tamiflu

Manufacturing[edit]

Oseltamivir is marketed by Genentech 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 6 mg/ml).[17][73]

See also[edit]

References[edit]

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Further reading[edit]

External links[edit]