Use Of Oseltamivir(Anti Flu)

Summary

Oseltamivir(Anti flu) is a neuraminidase inhibitor used in the prophylaxis and treatment of influenza.

Background

Oseltamivir (marketed as the product TamifluⓇ), is an antiviral neuraminidase inhibitor used for the treatment and prophylaxis of infection with influenza viruses A (including pandemic H1N1) and B. Oseltamivir exerts its antiviral activity by inhibiting the activity of the viral neuraminidase enzyme found on the surface of the virus, which prevents budding from the host cell, viral replication, and infectivity.

The clinical benefit of the use of oseltamivir is greatest when administered within 48 hours of the onset of influenza symptoms since effectiveness decreases significantly after that point in time; there is generally no benefit in use beyond 48 hours for healthy, low-risk individuals as influenza is a self-limiting illness. However, antiviral treatment might be beneficial when initiated after 48 hours for patients with severe, complicated, or progressive illness or for hospitalized patients. According to the CDC, data from clinical trials and observational studies have demonstrated that early antiviral treatment can shorten the duration of fever and illness symptoms, and may reduce the risk of some complications (including pneumonia and respiratory failure). They recommend the use of oseltamivir in people with a higher risk of developing complications including children younger than 2 years, people over 65 years, people with some chronic conditions or immunosuppression, pregnant women, residents of long term care facilities, and indigenous communities for example.

The benefits of oseltamivir use are controversial; a 2014 Cochrane Review of the evidence found that oseltamivir treatment had limited benefit. The authors concluded that oseltamivir use in healthy adults had small, non-specific effects on symptoms (where the time to first alleviation of symptoms was only reduced from 7 to 6.3 days), it had no effect on hospitalizations, and that there was no evidence for any reductions in complications of influenza such as pneumonia. Due to the risk of adverse effects such as nausea, vomiting, psychiatric effects, and renal adverse events in adults and vomiting in children, the harms are generally considered to outweigh the small clinical benefit of the use of oseltamivir.

Notably, in 2017, the World Health Organization downgraded oseltamivir from its essential medicines list from a "core" drug to a "complementary" drug, due to limited cost-effectiveness. Yearly vaccination with the influenza vaccine is still considered the best preventative measure.

Structure

Indication

According to FDA prescribing information, oseltamivir is indicated for the treatment of acute, uncomplicated illness due to influenza A and B infection in patients 2 weeks of age and older who have been symptomatic for no more than 48 hours. In particular, this agent is indicated in adults and children including full-term neonates who present with symptoms typical of influenza when the influenza virus is circulating in the community. Efficacy has been demonstrated when treatment is initiated within two days of the first onset of symptoms.

Oseltamivir is also indicated for the prophylaxis of influenza in patients one year and older. Specifically, post-exposure prevention in individuals one year of age or older following contact with a clinically diagnosed influenza case when influenza virus is circulating in the community qualifies for such prophylactic therapy. Oseltamivir would only be indicated for the post-exposure prevention of influenza in infants less than 1 year of age during a pandemic influenza outbreak.

Pharmacodynamics

There have been postmarketing reports of delirium and abnormal behavior leading to injury, and in some cases resulting in fatal outcomes, in patients with influenza who were receiving oseltamivir. Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made but they appear to be uncommon based on oseltamivir. These events were reported primarily among pediatric patients and often had an abrupt onset and rapid resolution. The contribution of oseltamivir to these events has not been established. Influenza can be associated with a variety of neurologic and behavioral symptoms that can include events such as hallucinations, delirium, and abnormal behavior, in some cases resulting in fatal outcomes. These events may occur in the setting of encephalitis or encephalopathy but can occur without the obvious severe disease.

Mechanism of action

Oseltamivir phosphate is a pro-drug of the active metabolite (oseltamivir carboxylate) which is a potent and selective inhibitor of influenza virus neuraminidase enzymes, which are glycoproteins found on the virion surface. Viral neuraminidase enzyme activity is important for viral entry into uninfected cells, for the release of recently formed virus particles from infected cells, and for the further spread of the infectious virus in the body. Oseltamivir activity reduces viral shedding and infectivity.

Oseltamivir is effective against viral neuraminidases of influenza A (including pandemic H1N1) and influenza B.

Absorption

Oseltamivir is readily absorbed from the gastrointestinal tract after oral administration of oseltamivir phosphate and is extensively converted by predominantly hepatic esterases to the active metabolite oseltamivir carboxylate. At least 75 % of an oral dose reaches the systemic circulation as the active metabolite. Exposure to the pro-drug is less than 5 % relative to the active metabolite. Plasma concentrations of both pro-drug and active metabolites are proportional to dose and are unaffected by co-administration with food. Pharmacokinetic parameters following twice-daily dosing of oseltamivir 75mg capsules are as follows: Cmax of oseltamivir and oseltamivir carboxylate were found to be 65ng/mL and 348ng/mL, respectively, while AUC (0-12h) of oseltamivir and oseltamivir carboxylate were found to be 112ng·h/mL and 2719ng·h/mL, respectively.

Volume of distribution

The mean volume of distribution at steady state of the oseltamivir carboxylate ranges approximately between 23 and 26 liters in humans, a volume that is roughly equivalent to extracellular body fluid. Since neuraminidase activity is extracellular, oseltamivir carboxylate distributes to all sites of influenza virus spread.

Protein binding

The binding of the active oseltamivir carboxylate metabolite to human plasma protein is negligible at approximately 3 % while the binding of oseltamivir to human plasma protein is 42%, which is insufficient to cause significant displacement-based drug interactions.

Metabolism

Oseltamivir is extensively converted to the active metabolite, oseltamivir carboxylate, by esterases located predominantly in the liver. Oseltamivir carboxylate is not further metabolized. Neither oseltamivir nor oseltamivir carboxylate is a substrate for, or inhibitor of, cytochrome P450 isoforms. No phase 2 conjugates of either compound have been identified in vivo.

Hover over products below to view reaction partners

• Oseltamivir

  • Oseltamivir carboxylase

Route of elimination

Following absorption, oseltamivir is more than 90 % eliminated through conversion to oseltamivir carboxylate and subsequent elimination entirely through renal excretion. During clinical studies, less than 20 % of the oral radiolabelled dose was found to be eliminated in faeces.

Half-life

Plasma concentrations of oseltamivir declined with a half-life of 1 to 3 hours in most subjects after oral administration, although plasma concentrations of oseltamivir carboxylate declined with a half-life of 6 to 10 hours in most subjects after oral administration.

Clearance

Renal clearance (18.8 l/h) of the drug exceeds the glomerular filtration rate (7.5 l/h) indicating that tubular secretion occurs in addition to glomerular filtration.

Toxicity

Reports of overdoses with oseltamivir have been received from clinical trials and during postmarketing experience. In the majority of cases reporting an overdose, no adverse reactions were reported. Adverse reactions reported following overdose were similar in nature to those observed with therapeutic doses of oseltamivir.

Food Interactions

• Take with or without food. Co-administration with food does not affect pharmacokinetics but may enhance tolerability.

Affected organisms

• Influenza A virus

• Influenza B virus