DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Table 58–3
Pharmacological Characteristics of Antivirals for Influenza
AMANTADINE RIMANTADINE ZANAMIVIR OSELTAMIVIR
Spectrum (types of influenza) A A A, B A, B
Route/formulations Oral (tablet/ Oral (tablet/syrup) Inhaled (powder) Oral (capsule/
capsule/syrup) Intravenous a syrup)
Intravenous a
Oral bioavailability > 90% > 90% < 5% b 80% c
Effect of meals on AUC Negligible Negligible Not applicable Negligible
Elimination t 1/2
, h 12-18 24-36 2.5-5 6-10 c
Protein binding, % 67% 40% < 10% 3% c
Metabolism, % < 10% ~75% Negligible Negligible
Renal excretion, % >90% ~25% 100% 95% c
(parent drug)
Dose adjustments Cl cr
≤ 50 Cl cr
≤ 10 None d Cl cr
≤ 30
Age ≥ 65 yrs Age ≥ 65 years
A fifth agent, permavir, is investigational in the U.S. and approved in Japan at a dose of 600 mg intravenously once daily in adults. Its elimination is
primarily renal, with dosage adjustment required for renal insufficiency.
a
Investigational at present. b Systemic absorption 4-17% after inhalation. c For antivirally active oseltamivir carboxylate. d Inhaled formulation only.
Cl cr
, creatinine clearance
home residents; short-term use (7-10 days) protects against influenza
in household contacts (Schirmer and Holodniy, 2009).
Because of the global development of resistance of H1N1
seasonal influenza, treatment recommendations issued by the CDC
for the 2008–2009 influenza season required the co-administration
of an adamantine and a neuraminidase inhibitor. An intravenous formulation
of oseltamivir is being evaluated in adults and children
under the 2009 EUA. Until recently, oseltamivir was only licensed
for patients >2 years of age; however, with the introduction of 2009
nH1N1, an EUA allows for therapy for all ages (Centers for Disease
Control and Prevention, 2009).
Zanamivir
Chemistry and Antiviral Activity. Zanamivir (Figure
58–4) is a sialic acid analog that potently and specifically
inhibits the neuraminidases of influenza A and
B viruses.
Depending on the strain, zanamivir competitively
inhibits influenza neuraminidase activity at
concentrations of ~0.2-3 ng/mL but affects neuraminidases
from other pathogens and mammalian
sources only at 106-fold higher concentrations.
Zanamivir inhibits in vitro replication of influenza A
and B viruses, including amantadine- and rimantadine-resistant
strains and several oseltamivir-resistant
variants. It is active after topical administration
in animal influenza models.
Mechanisms of Action and Resistance. Like oseltamivir,
zanamivir inhibits viral neuraminidase and thus causes
viral aggregation at the cell surface and reduced spread
of virus within the respiratory tract (Eiland and
Eiland, 2007).
In vitro selection of viruses resistant to zanamivir is associated
with mutations in the viral hemagglutinin and/or neuraminidase.
Hemagglutinin variants generally have mutations in or
near the receptor binding site that make them less dependent on
neuraminidase action for release from cells in vitro, although they
typically retain susceptibility in vivo. Hemagglutinin variants are
cross-resistant to other neuraminidase inhibitors. Neuraminidase
variants contain mutations in the enzyme active site that diminish
binding of zanamivir, but the altered enzymes show reduced activity
or stability. Zanamivir-resistant variants usually have decreased
infectivity in animals. Resistance has not been documented in
immunocompetent hosts to date but has been seen rarely in highly
immunocompromised patients (Eiland and Eiland, 2007).
Absorption, Distribution, and Elimination. The oral bioavailability
of zanamivir is low (<5%) (Table 58–3), and the commercial form
is delivered by oral inhalation of dry powder in a lactose carrier. The
proprietary inhaler device is breath-actuated and requires a cooperative
patient. Following inhalation of the dry powder, ~15% is
deposited in the lower respiratory tract and ~80% in the oropharynx.
Overall bioavailability is 4-17%, and plasma levels after 10-mg
inhaled doses average ~35-100 ng/mL in adults and children. Median
zanamivir concentrations in induced sputum samples are 1336
ng/mL at 6 hours and 47 ng/mL at 24 hours after a single 10-mg
dose in healthy volunteers. The plasma t 1/2
of zanamivir averages
2.5-5 hours after oral inhalation but only 1.7 hours following intravenous
dosing. Over 90% is eliminated in the urine as the parent
compound (Eiland and Eiland, 2007).
Untoward Effects. Orally inhaled zanamivir generally is well tolerated
in ambulatory adults and children with influenza. Wheezing and
bronchospasm have been reported in some influenza-infected patients