Zanamivir
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| Clinical data | |
|---|---|
| Other names | 5-acetamido- 4-guanidino- 6-(1,2,3-trihydroxypropyl)- 5,6-dihydro- 4H-pyran- 2-carboxylic acid |
| Pregnancy category | |
| Routes of administration | Inhalation |
| ATC code | |
| Legal status | |
| Legal status |
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| Pharmacokinetic data | |
| Bioavailability | 2% (oral) |
| Protein binding | <10% |
| Metabolism | Negligible |
| Elimination half-life | 2.5–5.1 hours |
| Excretion | Renal |
| Identifiers | |
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| CAS Number | |
| PubChem CID | |
| DrugBank | |
| CompTox Dashboard (EPA) | |
| ECHA InfoCard | 100.218.632 |
| Chemical and physical data | |
| Formula | C12H20N4O7 |
| Molar mass | 332.31 g/mol g·mol−1 |
| (verify) | |
Zanamivir (INN) (Template:PronEng) is a neuraminidase inhibitor used in the treatment and prophylaxis of Influenzavirus A and Influenzavirus B. Zanamivir was the first neuraminidase inhibitor commercially developed. It is currently marketed by GlaxoSmithKline under the trade name Relenza.
According to the CDC, No flu, seasonal or pandemic has shown any signs of resistance to Zanamivir.[1]
As stated on the Relenza.com website, "RELENZA is approved to help to prevent getting (prophylaxis) influenza A and B in children and adults age 5 years and older in community and household settings. Using an antiviral medicine like RELENZA can make you less likely to get the flu. Talk to your doctor to find out if RELENZA is right for you." Relenza is approved, by the FDA, for treating (not preventing) the flu in patients over the age of 7.
History
Zanamivir was discovered in 1989 by scientists led by Mark von Itzstein, at the Victorian College of Pharmacy, presently known as Monash Institute of Pharmaceutical Science, Monash University, in collaboration with the CSIRO and scientists at Glaxo, UK. The discovery was funded initially by the Australian biotechnology company Biota and was part of Biota's ongoing program to develop antiviral agents through rational drug design. Its strategy relied on the availability of the structure of influenza neuraminidase, by X-ray crystallography. It was also known, as far back as 1974, that 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (DANA), a sialic acid analogue, was an inhibitor of neuraminidase.[2] Sialic acid (N-acetyl neuraminic acid, NANA), the substrate of neuraminidase, is itself a mild inhibitor of the enzyme, but the dehydrated derivative DANA, a transition-state analogue, is a better inhibitor.
Computational chemistry techniques were used to probe the active site of the enzyme, in an attempt to design derivatives of DANA that would bind tightly to the aminoacid residues of the catalytic site, and so would be potent and specific inhibitors of the enzyme. The software GRID from Molecular Discovery was used to determine energetically favourable interactions between various functional groups and residues in the catalytic site canyon. This showed there was a negatively charged zone in the neuraminidase active site that aligned with the C4 hydroxyl group of DANA. This hydroxyl was therefore replaced with a positively charged amino group; the 4-amino DANA was 100 times better an inhibitor than DANA, owing to the formation of a salt bridge with a conserved glutamic acid (119) in the active site. It was also noticed that Glu 119 was at the bottom of a conserved pocket in the active site just big enough to accommodate a more basic functional positively charged group, such as a guanidino group, which was also larger than the amino group.(Professor Graeme Laver,2007). Zanamivir, a transition-state analogue inhibitor of neuraminidase, was the result.[3]
Indications
The treatment of infections caused by Influenzavirus A and Influenzavirus B.
Contraindications
Oral dosing of zanamivir is ineffective, limiting dosing to the inhaled route. This restricts its usage, as treating asthmatics could induce bronchospasm.[4] The FDA has issued a Public Health Advisory warning that it has received some reports of respiratory problems following inhalation of zanamivir by patients with underlying asthma or chronic obstructive pulmonary disease. The zanamivir package insert contains precautionary information regarding risk of bronchospasm in patients with respiratory disease.[5]
Adverse effects
Zanamivir (Relenza) is specific to the influenza virus, has not been known to cause toxic effects, and does not spread around through the body's systemic circulation. It also shows no signs of viral resistance. However, due to a lack of reports or evidence about its toxicity, the FDA does not license it for use, as a treatment for the flu, in children under 7 years of age.
The Relenza.com website does state, "RELENZA is approved to help to prevent getting (as a prophylaxis for) influenza A and B in children and adults age 5 years and older in community and household settings. Using an antiviral medicine like RELENZA can make you less likely to get the flu. Talk to your doctor to find out if RELENZA is right for you." These two statements only appear to conflict as to the minimum age of the patient, they do not conflict. Consult your doctor prior to starting a Relenza treatment regimine in young children, as well as adults.
Pharmacokinetics
The bioavailability of zanamivir is 2 percent. After inhalation, zanamivir is concentrated in the lungs and oropharynx, where up to 15 percent of the dose is absorbed and excreted in urine.[6]
Pharmacodynamics
Influenza, commonly known as the flu, is caused by a virus which targets the body's respiratory cells and damages the lining of the respiratory tract, leading to swelling and inflammation of the tract. Influenza spreads rapidly by replicating itself inside the host cell, producing hundreds of copies of the virus in a short period. In approximately an hour the virus can destroy the host cell and propel its replications out into the body to find new host cells. For some people, the flu and its complications can be very serious, even fatal.
Zanamivir works by binding to the active site of the neuraminidase protein, rendering the influenza virus unable to escape its host cell and infect others.[7] It is also an inhibitor of influenza virus replication in vitro and in vivo. In clinical trials it was found that zanamivir was able to reduce the time to symptom resolution by 1.5 days if therapy was started within 48 hours of the onset of symptoms.
Legal status
The drug is approved for use for the prevention and treatment of influenza in persons over the age of 7 in the United States, Canada, European Union and many other countries. Is is not recommended for people with respiratory problems and ailments.
Biota, being only a small company, was not able to bring zanamivir to market by itself. In 1990, zanamivir patent rights were licensed to Glaxo, now GlaxoSmithKline (GSK). In 1999, the product was approved for marketing in the USA and subsequently has been registered by GSK in a total of 70 countries (GlaxoSmithKline News release, 2006). Zanamivir is delivered via Glaxo's proprietary Diskhaler inhalation device. The license agreement entitled Biota to receive a 7% royalty on Glaxo's sales of zanamivir.
Commercial issues
Although zanamivir was the first neuraminidase inhibitor to the market, it had only a few months lead over the second entrant, oseltamivir (Tamiflu), with an oral tablet formulation.
When first marketed in the USA in 1999/00, zanamivir captured only 25% of the influenza antiviral market, despite a huge promotional campaign. By the end of that season, Tamiflu was outselling zanamivir 3:1. During that season, zanamivir experienced worldwide safety warnings involving the risk of bronchospasm and death. Glaxo then reduced the marketing of zanamivir, and Tamiflu's dominance increased. More than US$20m worth of zanamivir sold by Glaxo in the first US season was returned to the company in the next two seasons because zanamivir's actual sales to patients were far less than expected, highlighting the fact that the results of the first season were even worse than first thought.
Biota commenced legal proceedings in 2004 alleging that Glaxo's reduced marketing of zanamivir was a breach of contract. Biota claimed approximately A$700m from Glaxo. After Biota spent four years trying to progress its case, and incurring A$50m in legal costs, the company abandoned the claim in July 2008, recovering only A$20m including legal costs following settlement at mediation. Biota had refused an earlier tactical offer from Glaxo of A$75m plus legal costs.
According to the CDC, Tamiflu, zanamivir’s main competitor, is not as effective at treating the Influenza viruses as zanamivir, especially in H1N1 Seasonal Flu. In Fact, Tamiflu showed that 99.6% of the tested strains of seasonal H1N1 flu were resistant to Tamiflu while there have been absolutely zero flu samples seasonal or pandemic that show resistance to zanamivir.[8]
On September 10, 2009 in the CDC's report MMWR under the title "Update: Influenza Activity --- United States, April--August 2009" the CDC wrote, "Of 1,372 pandemic H1N1 viruses tested for antiviral resistance at CDC from ill persons in the United States, 1,364 (99.4%) have been susceptible to oseltamivir [Tamiflu]. All eight pandemic H1N1 viruses found to be resistant to oseltamivir were obtained from persons taking oseltamivir for treatment or prophylaxis at the time of specimen collection. All viruses tested have been susceptible to zanamivir, and all have been resistant to amantadine and rimantadine."
In August 2006, Germany announced that it would buy 1.7 million doses of zanamivir, as part of its preparation strategy against bird flu. "Germany's purchase shows that countries are starting to take a balanced view of influenza preparedness," says Simon Tucker, head of research at Melbourne-based Biota, where zanamivir was originally developed.[7]
In April 2009 many cases of swine flu (H1N1 type virus) were reported in USA and Mexico. Zanamavir is one of only two drugs that are prescribed to treat it. A study published in June 2009 emphasized the urgent need for augmentation of oseltamivir (Tamiflu) stockpiles, with additional antiviral drugs including zanamivir, based on an evaluation of the performance of these drugs in the scenario that the 2009 H1N1 swine flu neuraminidase (NA) were to acquire the Tamiflu-resistance (His274Tyr) mutation which is currently widespread in 99.6% of all tested seasonal H1N1 strains.[9]
Bulk orders of Tamiflu from the United Kingdom, France and other countries to cover 20% or more of their population are pushing Roche's production capacity to the limit. But zanamivir, which was the first neuraminidase inhibitor on the market, claims only one percent of the growing flu drug market.
Tamiflu-resistant strains have also appeared in the European Union, which remain sensitive to zanamivir.[10][11]
Developments from zanamivir
Zanamivir was the first of the neuraminidase inhibitors. Despite the limited commercial success of this drug, the work and strategies employed in the development of zanamivir were important first-steps in the development of further members of this class including oseltamivir and the candidate drug RWJ-270201 (Phase I trials).
Recently, the reported oseltamivir-resistance H5N1 virus neuraminidase still retaining susceptibility to zanamivir indicates that the structure of zanamivir has some advantages over oseltamivir in binding to the active pocket of H5N1 neuraminidase.[12][10][11]
As a proven anti-influenza drug target, neuraminidase continues to be attractive for the development of new inhibitors. The crystal structure of H5N1 avian influenza neuraminidase (PDB code: 2HTY) provides the three-dimensional structural information and opportunity for finding new inhibitors in this regard, because the existing inhibitors, such as oseltamivir and zanamivir, were developed based on different structures of neuraminidase, such as subtypes N9, N2, and type B genus of influenza virus.
References
- ^ "2008-2009 Influenza Season Week 32 ending August 15, 2009 " CDC, Aug. 24, 2009
- ^ Meindl P, Bodo G, Palese P, Schulman J, Tuppy H (1974). "Inhibition of neuraminidase activity by derivatives of 2-deoxy-2,3-dehydro-N-acetylneuraminic acid". Virology. 58 (2): 457–63. doi:10.1016/0042-6822(74)90080-4. PMID 4362431.
{{cite journal}}:|access-date=requires|url=(help); Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ von Itzstein M, Wu WY, Kok GB; et al. (1993). "Rational design of potent sialidase-based inhibitors of influenza virus replication". Nature. 363 (6428): 418–23. doi:10.1038/363418a0. PMID 8502295.
{{cite journal}}:|access-date=requires|url=(help); Explicit use of et al. in:|author=(help); Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Hayden FG (2001). "Perspectives on antiviral use during pandemic influenza". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 356 (1416): 1877–84. doi:10.1098/rstb.2001.1007. PMC 1088564. PMID 11779387.
{{cite journal}}:|access-date=requires|url=(help); Unknown parameter|month=ignored (help) - ^ http://www.fda.gov/cder/drug/advisory/influenza.htm FDA Advisory: Safe and appropriate use of Influenza drugs
- ^ Moscona A (2005). "Neuraminidase inhibitors for influenza". The New England Journal of Medicine. 353 (13): 1363–73. doi:10.1056/NEJMra050740. PMID 16192481.
{{cite journal}}:|access-date=requires|url=(help); Unknown parameter|month=ignored (help) - ^ a b Cyranoski D (2005). "Threat of pandemic brings flu drug back to life". Nature Medicine. 11 (9): 909. doi:10.1038/nm0905-909. PMID 16145557.
{{cite journal}}:|access-date=requires|url=(help); Unknown parameter|month=ignored (help) - ^ "2008-2009 Influenza Season Week 32 ending August 15, 2009 " CDC, Aug. 24, 2009
- ^ Venkataramanan Soundararajan, Kannan Tharakaraman, Rahul Raman, S. Raguram, Zachary Shriver, V. Sasisekharan, Ram Sasisekharan (9 June 2009). "Extrapolating from sequence — the 2009 H1N1 'swine' influenza virus". Nature Biotechnology. 27 (6): 510. doi:10.1038/nbt0609-510.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ a b Collins PJ, Haire LF, Lin YP, Liu J, Russell RJ, Walker PA, Skehel JJ, Martin SR, Hay AJ, Gamblin SJ. (2008). "Crystal structures of oseltamivir-resistant influenza virus neuraminidase mutants". Nature. 453: 1258. doi:10.1038/nature06956.
{{cite journal}}: CS1 maint: multiple names: authors list (link) Cite error: The named reference "collins" was defined multiple times with different content (see the help page). - ^ a b Garcia-Sosa AT, Sild S, Maran U. (2008). "Design of Multi-Binding-Site Inhibitors, Ligand Efficiency, and Consensus Screening of Avian Influenza H5N1 Wild-Type Neuraminidase and of the Oseltamivir-Resistant H274Y Variant". J. Chem. Inf. Model. 48 (10): 2074–2080. doi:10.1021/ci800242z. PMID 18847186.
{{cite journal}}: CS1 maint: multiple names: authors list (link) Cite error: The named reference "garcia-sosa" was defined multiple times with different content (see the help page). - ^ Du QS, Wang SQ, Chou KC (2007). "Analogue inhibitors by modifying oseltamivir based on the crystal neuraminidase structure for treating drug-resistant H5N1 virus". Biochemical and Biophysical Research Communications. 362 (2): 525–31. doi:10.1016/j.bbrc.2007.08.025. PMID 17707775.
{{cite journal}}:|access-date=requires|url=(help); Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link)
Further Reading
- Soundararajan V, Tharakaraman K, Raman R, Raguram S, Sasisekharan V, Sasisekharan R (2009). "Extrapolating from sequence--the 2009 H1N1 'swine' influenza virus". Nature Biotechnology. 27 (6): 510–3. doi:10.1038/nbt0609-510. PMID 19513050.
{{cite journal}}:|access-date=requires|url=(help); Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - Professor Graeme Laver,Flu drugs - pathway to discovery, Education in Chemistry, March 2007 <http://www.rsc.org/Education/EiC/issues/2007March/FluDrugsPathwayDiscovery.asp>