Medical Pharmacology Chapter 36:  Antiviral Drugs

• Antiviral Drugs

  • Anti-viral drugs with activity against influenza.

    • Two primary neuraminidase inhibitors (NAIs) are globally licensed for both treatment and influenza prevention.⁵ 

      • The first drug developed in this class was zanamivir (Relenza), followed by oseltamivir (Tamiflu).⁵ 

        •  

          Zanamivir (Relenza)

        •  

          Oseltamivir (Tamiflu)

      • These agents were developed by taking into account the structure of enzyme transition structural states involved in neuraminidase activity.

      • Zanamivir (Relenza) is administered by oral inhalation; whereas, oseltamivir (Tamiflu) is taken orally.⁵

        • These agents are examples of rational drug design, based on the crystalline structure of influenza virus sialidase (neuraminidase).⁶ 

          • The two potent inhibitors so identified proved not only to be inhibitors of the enzyme but also of the influenza virus in cell culture as well as in animal models.⁶ 

    • Oseltamivir (Tamiflu)

      •  

        Tamiflu

      • Some influenza variants exhibit resistance to oseltamivir carboxylate and these isolates show hemagglutinin and/or neuraminidase mutations.¹  

        • Commonly noted variants which reduce both infectivity and virulence involve mutations in N2 (neuraminidase 2 at position 292) and mutations at N1 (neuraminidase 1 at position 274).

        • A mutation associated with isolates resistant to oseltamivir (H275Y mutation) is due to a change from the amino acid histidine to tyrosine; however, in this case zanamivir-sensitivity is maintained.²

        • Some mutations result is loss of sensitivity to both oseltamivir and zanamivir, such as mutation 1223R corresponding to a change from the amino acid isoleucine to arginine.²

        • Seasonal influenza A (H1N1) may be nearly 100% oseltamivir resistant, worldwide.

          • Susceptibility to oseltamivir in swine influenza or novel H1N1 (nH1N1) remains intact.¹

      • Oseltamivir and zanamivir exhibit activity against both influenza A and influenza B viruses.³ 

        • For both drugs, early administration is important since viral replication is greatest between days 1-3 following symptom onset.³ 

          • The duration of the illness may be reduced by about 1-2 days.

            • Furthermore, influenza severity is also reduced and the likelihood of secondary complications in both adults and children is also decreased.

              • Oseltamivir has FDA approval for individuals one year and older. By contrast zanamivir is FDA approved in patients who are 7 years or older.³

      • Oseltamivir is a "prodrug", orally administered, and must be converted to an active form by liver esterases.³ 

        • Bioavailability of the carboxylate is about 80% with limited plasma protein binding.^1,3 

        • Food does not reduce oseltamivir carboxylate bioavailability, although food does have the benefit of decreasing the likelihood of gastrointestinal side effects.¹  

        • Oseltamivir half-life (t_½) is about 6-10 hours.

        • Elimination of oseltamivir and oseltamivir carboxylate, the active form, by the kidney occurs by both glomerular filtration and tubular secretion.^1,3 

          • Renal clearance of oseltamivir may be reduced by 50% when administered in the presence of probenecid.

        • Importantly, the serum concentration of the active metabolite of oseltamivir, oseltamivir carboxylate, increases with reduced renal function.

          • Accordingly, oseltamivir dosage may require adjustment in these patients.³

      • Oseltamivir:  Adverse Effects

        • Ingestion of oral oseltamivir may be associated with G.I. discomfort, including abdominal discomfort, nausea and infrequently emesis, secondary to local irritation.

          • These G.I. effects are described as mild to moderate and resolve in about a day or two, despite continual dosing.

            • As suggested earlier, these effects may be prevented or reduced by administering the drug with food.

        • Oseltamivir is not associated with clinically important drug-drug interactions.

        • Furthermore, oseltamivir neither impairs fertility or exhibits teratogenicity in animal studies.

          • Safety in pregnancy remains uncertain and accordingly this drug is categorized as pregnancy Category C.

      • Zanamivir (Relenza)

        • Zanamivir (Relenza) also inhibits viral neuraminidase, like oseltamivir, thus resulting in viral aggregation at the cell surface and reduction of viral spread.¹ 

          • Resistance to the action of zanamivir may be due to mutations in viral hemagglutinin and/or neuraminidase.¹  

          • Hemagglutinin variants exhibit mutations in or near the receptor binding site.

            • This localization makes these resistant isolates less dependent on neuraminidase activity for release from cells, at least in vitro and usually retain susceptibility in vivo.

            • Hemagglutinin variants tend also to be cross-resistant to other neuraminidase inhibitors.

        • Zanamavir:  Absorption and Bioavailability¹ 

          • Relatively low oral bioavailability of zanamivir (<5%) requires oral inhalation of dry powder, using a lactose carrier.

            •  

              Relenza Inhaler

            • The inhaler is breath-actuated, requiring cooperation from the patient.

              • After inhalation of the dry powder about 15% is localized in the lower respiratory tract with about 80% in the oropharynx.

                • Bioavailability is estimated at between 4% and 17%.

                  • Plasma half-life (t_½) of zanamivir is about 2.5-5 hours following oral inhalation.

                  • Plasma half-life (t_½) is reduced to about 1.7 hours after IV dosing.

                  • Greater than 90% of zanamivir is found unchanged in the urine.¹ 

          • Zanamavir:  Adverse Effects

            • Zanamivir is usually well tolerated in ambulatory adults and children with influenza.

              • In some influenza-infected individuals without established airway disease, orally inhaled zanamivir may cause wheezing and bronchospasm.

              • In patients with established asthma or COPD (chronic obstructive airway disease) orally inhaled zanamivir may induce significant decline in lung function, including those which result in fatal outcome.

                • Accordingly, zanamivir is typically not recommended for use in patients with underlying airway disorders because of this risk.

            • Zanamivir has not in preclinical studies been demonstrated to exhibit mutagenic, oncogenic, or teratogenic effects.

            • Zanamivir is classified as pregnancy Category C.