Oseltamivir (Tamiflu ) for Acute Influenza. John Collins Spring 2014 BME 270

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1 Oseltamivir (Tamiflu ) for Acute Influenza John Collins Spring 2014 BME 270

2 Key Points About Oseltamivir for Treating Acute Influenza Infections Influenza = RNA virus (replicates genome by RNA- dependent RNA polymerase) that infects the respiratory tracts of mammals (and intes@nes of birds) Although vaccina@on is the primary strategy for the preven@on of influenza, there are a number of likely scenarios (e.g., an@genic drid, slow vaccine produc@on, at- risk subpopula@ons) for which vaccina@on is inadequate and effec$ve an$viral agents would be of the utmost importance. Two classes of an@virals: adamantanes and neuraminidase inhibitors (adamantanes have toxic adverse effects on CNS; neuraminidase is a glycoside hydrolase enzyme on the surface of influenza) Phase III trial of Oseltamivir demonstrated 30% reduc@on in experiencing symptoms (if taken within 48 hours of onset of symptoms) Post- marke@ng studies (IMPACT) revealed much higher efficacy of Oseltamivir if taken within only 12 hours of onset of symptoms

3 Influenza Replication Cycle adamantane drugs inhibit M2 ion channel neuraminidase inhibitor drugs block surface enzyme

4 Molecular Targets (Mechanism of Action) Neuraminidase is required for cleaving hemagglutinin from sialic acid on the surfaces of infected cells

5 History Chinese star anise antivirals are necessary in addition to vaccines four current antiviral drugs: two adamantanes and two neuraminidase inhibitors realization of possible sialic acid transition-state analog as early as the 70 s... à but wasn t possible to develop effective inhibitor until knowledge of 3D structure of influenza neuraminidase enzyme (in the 90 s)

6 Chemical Properties Oseltamivir is a prodrug; first-pass liver metabolism converts the drug into its active carboxylate form via hepatic esterases Shikimic acid (deriva@ve from Chinese star anise)

7 Preclinical Evidence In vitro & In vivo

8 Pharmacokinetics in Humans For Zanamivir: 2% bioavailability, efficacious within ten seconds after administration, lung concentration reaches 1000x IC50 (favorable effects for minimizing resistance development in virus) Oseltamivir: 80% bioavailability; half-life of 6-10 hours; excreted primarily renally as its active carboxylate metabolite (no cytochrome P450 or glucuronosyltransferases; very high VD so it effectively leaves plasma distribution and reaches lungs, nasal passages, ears adverse reactions: well-tolerated; most studies report just as many adverse effects in treatment group compared to placebo-control group

9 Clinical Evidence Randomized, placebo- controlled, double blind study from January through March 1998 Sixty primary care and university health centers throughout the United States 629 healthy nonimmunized adults aged with respiratory illness of no more than 36 hours with temperature of > 38 C Randomized into 1 of 3 treatments groups: Oseltamivir 75 mg twice daily, Oseltamivir 150 mg twice daily, or placebo Outcome measurements: dura@on and severity of influenza illness Results: 374 (~60%) actually infected with influenza, dura@on of illness reduced by 30% and severity of illness reduced by 40%

10 Clinical Evidence (cont d)

11 Post-Marketing Surveillance & Modern Controversy Over Indications and Efficacy 2003 Immediate Possibility to Access Treatment (IMPACT) study: Treatment that started within the first 12 hours ader the onset of fever shortened the illness by more than three days, as compared with treatment that was started at 48 hours. The of treatment at shortened the illness 2014 Nature 508, : News in Focus commentary on the release of Jefferson et al. Cochrane reviews and BMJ reviews that meta- analyzed RCTs (strictly exclude studies) and reported no of efficacy for Tamiflu in reducing or severe (i.e., the main concerns during a pandemic outbreak) à government stockpiles = money down the drain?

12 References Moscona, Anne. "Neuraminidase inhibitors for influenza." New England Journal of Medicine (2005): He, George, Joseph Massarella, and Penelope Ward. "Clinical of the prodrug oseltamivir and its metabolite Ro " Clinical pharmacokine$cs 37.6 (1999): Treanor, John J., et al. "Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in acute influenza: a randomized controlled trial." Jama (2000): Das, Kalyan, et al. "Structures of influenza A proteins and insights into an@viral drug targets." Nature structural & molecular biology 17.5 (2010): Jefferson, T., et al. "Neuraminidase inhibitors for preven@ng and trea@ng influenza in healthy adults and children (Review)." (2014).