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

1608 amantadine or rimantadine treatment (200 mg/day for 5 days)
reduces the duration of fever and systemic complaints by 1-2 days,
speeds functional recovery, and sometimes decreases the duration of
virus shedding (Schmidt, 2004). In children, rimantadine treatment
may be associated with less illness and lower viral titers during the
first 2 days of treatment, but rimantadine-treated children have more
prolonged shedding of virus. The usual regimen in children (≥1 year
of age) is 5 mg/kg/day, up to 150 mg, administered once or twice daily.
Resistant variants have been recovered from ~30% of treated
children or outpatient adults by the fifth day of therapy (Schmidt,
2004). Resistant variants also arise commonly in immunocompromised
patients (Englund et al., 1998). Illnesses owing to apparent
transmission of resistant virus associated with failure of drug prophylaxis
have been documented in contacts of drug-treated ill persons in
households and in nursing homes (Schmidt, 2004). Resistant variants
appear to be pathogenic and can cause typical disabling influenza.
Although both drugs are useful for the prevention and treatment
of infections caused by influenza A virus, vaccination against
influenza is a more cost-effective means of reducing disease burden.
The utility of the amantadines has been limited by the development
of resistance. Amantadine and rimantadine are active only against
susceptible influenza A viruses (not influenza B); rimantadine is
4- to 10-fold more active than amantadine. Currently, virtually all
H3N2 strains of influenza circulating worldwide are resistant to
these drugs. Resistance to these drugs results from a mutation in the
RNA sequence encoding for the M2 protein transmembrane domain
(Schmidt, 2004), and resistant isolates typically appears in the
treated patient within 2-3 days of starting therapy.
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
Oseltamivir
Chemistry and Antiviral Activity. Oseltamivir carboxylate
(Figure 58–4) is a transition-state analog of sialic
acid that is a potent selective inhibitor of influenza A
and B virus neuraminidases. Oseltamivir phosphate is
an ethyl ester prodrug that lacks antiviral activity.
Oseltamivir carboxylate has an antiviral spectrum
and potency similar to that of zanamivir. It inhibits
amantadine and rimantadine-resistant influenza A
viruses and some zanamivir-resistant variants.
Mechanisms of Action and Resistance. Influenza neuraminidase
cleaves terminal sialic acid residues and
destroys the receptors recognized by viral hemagglutinin,
which are present on the cell surface, in progeny
virions, and in respiratory secretions (Schirmer and
Holodniy, 2009). This enzymatic action is essential for
release of virus from infected cells. Interaction of
oseltamivir carboxylate with the neuraminidase causes
a conformational change within the enzyme’s active site
and inhibits its activity. Inhibition of neuraminidase
activity leads to viral aggregation at the cell surface and
reduced virus spread within the respiratory tract.
Influenza variants selected in vitro for resistance to oseltamivir
carboxylate contain hemagglutinin and/or neuraminidase mutations.
The most commonly recognized variants (mutations at positions 292
in N2 and 274 in N1 neuraminidases) have reduced infectivity and
virulence in animal models. Outpatient oseltamivir therapy has been
associated with recovery of resistant variants in ~0.5% of adults and
5.5% of children; a higher frequency (~18%) occurs in hospitalized
children. Seasonal influenza A (H1N1) has become virtually 100%
resistant to oseltamivir worldwide (Moscona, 2009; Schirmer and
Holodniy, 2009). Importantly, novel H1N1 (nH1N1 or swine
influenza) remains susceptible to oseltamivir.
Absorption, Distribution, and Elimination. Oral oseltamivir phosphate
is absorbed rapidly (Table 58–3) and cleaved by esterases in
the GI tract and liver to the active carboxylate. Low blood levels of
the phosphate are detectable, but exposure is only 3-5% of that of the
metabolite. The bioavailability of the carboxylate is estimated to be
~80%. The time to maximum plasma concentrations of the carboxylate
is ~2.5-5 hours. Food does not decrease bioavailability but
reduces the risk of GI intolerance. After 75-mg doses, peak plasma
concentrations average 0.07 μg/mL for oseltamivir phosphate and
0.35 μg/mL for the carboxylate. The carboxylate has a volume of
distribution similar to extracellular water. Bronchoalveolar lavage
levels in animals and middle ear fluid and sinus concentrations in
humans are comparable with plasma levels. Following oral administration,
the plasma t 1/2
of oseltamivir phosphate is 1-3 hours; that
of the carboxylate is 6-10 hours. Both the prodrug and active
metabolite are eliminated primarily unchanged through the kidney.
Probenecid doubles the plasma t 1/2
of the carboxylate, which indicates
tubular secretion by the anionic pathway. Children <2 years of
age exhibit age-related changes in oseltamivir carboxylate clearance
and total drug exposure (Kimberlin et al., 2009).
Untoward Effects. Oral oseltamivir is associated with nausea,
abdominal discomfort, and, less often, emesis, probably owing to
local irritation. GI complaints usually are mild to moderate in intensity,
typically resolve in 1-2 days despite continued dosing, and are
preventable by administration with food. The frequency of such
complaints is ~10-15% when oseltamivir is used for the treatment of
influenza illness and <5% when used for prophylaxis. An increased
frequency of headache was reported in one prophylaxis study in elderly
adults.
Oseltamivir phosphate and the carboxylate do not interact
with CYPs in vitro. Their binding to protein is low. No clinically significant
drug interactions have been recognized to date. Oseltamivir
does not appear to impair fertility or to be teratogenic in animal studies,
but safety in pregnancy is uncertain (pregnancy Category C).
Very high doses have been associated with increased mortality, perhaps
related to increased brain concentrations, in unweaned rats.
Therapeutic Uses. Oral oseltamivir is effective in the treatment and
prevention of influenza A and B virus infections.
Treatment of previously healthy adults (75 mg twice daily for
5 days) or children 1-12 years of age (weight-adjusted dosing) with
acute influenza reduces illness duration by ~1-2 days, speeds functional
recovery, and reduces the risk of complications leading to
antibiotic use by 40-50% (Whitley et al., 2001). Treatment is associated
with approximate halving of the risk of subsequent hospitalization
in adults (Kaiser et al., 2003). When used for prophylaxis
during the typical influenza season, oseltamivir (75 mg once daily)
is effective (~70-90%) in reducing the likelihood of influenza illness
in both unimmunized working adults and in immunized nursing