Oseltamivir (INN) (IPA: ) is an antiviral drug used in the treatment and prophylaxis of both Influenzavirus A and Influenzavirus B. Like zanamivir, oseltamivir is a neuraminidase inhibitor, acting as a transition-state analogue inhibitor of influenza neuraminidase and thereby preventing new viruses from emerging from infected cells.
Oseltamivir was the first orally active neuraminidase inhibitor commercially developed. It is a prodrug, which is hydrolysed hepatically to the active metabolite, the free carboxylate of oseltamivir (GS4071). It was developed by Gilead Sciences and is currently marketed by Hoffmann-La Roche (Roche) under the trade name Tamiflu.
With increasing fears about the potential for a new influenza pandemic, oseltamivir has received substantial media attention. Production capacity is limited, and governments are stockpiling the drug.
Indications and dosage
Oseltamivir is indicated for the treatment of infections due to influenza A and B virus in people at least one year of age, and prevention of influenza in people at least 1 year or older. The usual adult dosage for treatment of influenza is 75 mg twice daily for 5 days, beginning within 2 days of the appearance of symptoms and with decreased doses for children and patients with renal impairment. Oseltamivir 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. (Roche, 2005; Rossi, 2006)
Use in avian influenza
It has been suggested that higher doses and longer durations of therapy should be used for treatment of patients with H5N1-type influenza A virus infection (avian influenza). It has been found that the standard recommended dose incompletely suppresses viral replication in at least some patients with H5N1 influenza, rendering therapy ineffective and increasing the risk of viral resistance. (de Jong et al., 2005)
Co-administration with probenecid
It has been suggested that co-administration of oseltamivir with probenecid could extend the limited supply of oseltamivir. Probenecid reduces renal excretion of the active metabolite of oseltamivir. One study showed that 500 mg of probenicid given every six hours doubled both the peak plasma concentration (Cmax) and the half-life of oseltamivir, increasing overall systemic exposure (AUC) by 2.5-fold. (Hill et al., 2002) Although the evidence for this interaction comes from a study by Roche, it was publicised only in October 2005 by a doctor who had reviewed the data (Butler, 2005). Probenecid was used in similar fashion during World War II to extend limited supplies of penicillin, and is still currently used to increase penicillin concentrations in serious infections.
Common adverse drug reactions (ADRs) associated with oseltamivir therapy include: nausea, vomiting, diarrhoea, abdominal pain, and headache. Rare ADRs include: hepatitis and elevated liver enzymes, rash, allergic reactions including anaphylaxis, and Stevens-Johnson syndrome. (Rossi, 2006)
Various other ADRs have been reported in postmarketing surveillance including: toxic epidermal necrolysis, cardiac arrhythmia, seizure, confusion, aggravation of diabetes, and haemorrhagic colitis.
In May 2004, the safety division of Japan's health ministry ordered changes to the literature accompanying oseltamivir to add neurological and psychological disorders as possible adverse effects, including: impaired consciousness, abnormal behavior, and hallucinations. Various cases of psychological disorders were associated with oseltamivir therapy between 2000–2004, including several deaths.
On 2005-11-18 the United States Food and Drug Administration (FDA) issued a report regarding the paediatric safety of oseltamivir, which stated that there was insufficient evidence to claim a causal link between oseltamivir use and the deaths of 12 Japanese children (only two from neurological problems). However, it was recommended that a warning was added to the Product Information regarding rashes associated with oseltamivir therapy (Pediatric Advisory Committee, 2005).
Mode of action
Oseltamivir is a neuraminidase inhibitor. By blocking the activity of the neuraminidase, Oseltamivir prevents new viral particles from being released by infected cells.
As with other antivirals, resistance to the agent was expected with widespread use of oseltamivir, though the emergence of resistant viruses was expected to be less frequent than with amantadine or rimantadine. The resistance rate reported during clinical trials up to July 2004 was 0.33% in adults, 4.0% in children, and 1.26% overall. Mutations conferring resistance are single amino acid residue substitutions in the neuraminidase enzyme (Ward et al., 2005).
Mutant H3N2 influenza A virus isolates resistant to oseltamivir were found in 18% of a group of 50 Japanese children treated with oseltamivir (Kiso et al., 2004). This rate was similar to another study where resistant isolates of H1N1 influenza virus were found in 16.3% of another cohort of Japanese children (Ward et al., 2005). 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. (2004) claim to have used more rigorous detection techniques than previous studies. Third, the dosage regimen in Japan is different from that of other nations, and some children may have been given a suboptimal dosage of oseltamivir.
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 (Le et al., 2005; World Health Organization, 2005).
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 that 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 Tamiflu could lead to under-dosage and thus the emergence of resistant strains of H5N1.
Resistance is of concern in the scenario of an influenza pandemic, since resistance is more likely to develop due to the potentially longer duration of infection by novel viruses. Kiso et al. (2004) suggest that "a higher prevalence of resistant viruses should be expected" during a pandemic.
The genetic sequence for the neuraminidase enzyme is highly conserved across virus strains. This means that there are relatively few variations, and there is also evidence that variations that do occur tend to be less "fit." Thus, mutations that convey resistance to oseltamivir may also tend to cripple the virus by giving it an otherwise less-functional enzyme. The lack of variation in neuraminidase gives two advantages to oseltamivir and zanamivir, the drugs that target that enzyme. First, these drugs work on a broader spectrum of influenza strains. Second, the development of a robust, resistant virus strain appears to be less likely (Ward et al., 2005). It is worth noting that the oseltamivir-resistant strains detected by Kiso et al. (2004) all appeared within individual children after treatment with oseltamivir – the children did not catch the resistant strains in human-to-human or bird-to-human transmission.
Oseltamivir appears to be active against canine parvovirus, feline panleukopenia, the canine respiratory complex known as "kennel cough," and the emerging disease dubbed "canine flu", an equine virus that began affecting dogs in 2005. Veterinary investigation of its use for canine parvo and canine flu is ongoing, but many shelters and rescue groups have reported great success employing oseltamivir in the early stages of these illnesses.
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