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

1658 with an intravenous dose (Dando and Perry, 2003). Pharmacokinetics
of the subcutaneous drug are not affected by site of injection.
The major route of elimination for enfuvirtide has not been
determined; only a deamidated metabolite at the C-terminal phenylalanine
has been detected (Dando and Perry, 2003). The mean elimination
t 1/2
of parenteral drug is 3.8 hours, necessitating twice-daily
administration. Enfuvirtide is 98% bound to plasma proteins, mainly
albumin.
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
Untoward Effects. The most prominent adverse effects of enfuvirtide
are injection-site reactions. About 98% of patients develop local side
effects including pain, erythema, and induration at the site of injection;
80% of patients develop nodules or cysts (Dando and Perry,
2003). Between 4% and 5% of patients discontinue treatment because
of local reactions. Use of enfuvirtide has been associated with a
higher incidence of lymphadenopathy and pneumonia in at least one
study. Whether these are direct drug effects, a secondary consequence
of drug-related immune dysfunction, or effects from another mechanism
is the subject of investigation. Enfuvirtide suppresses interleukin-12
production in vitro by >90% at concentrations equal to or
less than those required to inhibit HIV replication (Braun et al., 2001);
the role this might play in clinical immunosuppression is unclear.
Precautions and Interactions. Enfuvirtide is not metabolized to a
significant extent and not known to alter the concentrations of any coadministered
drugs. Ritonavir, rifampin, or ritonavir plus saquinavir
did not alter enfuvirtide concentrations (Dando and Perry, 2003).
Therapeutic Use. Enfuvirtide (FUZEON) is FDA-approved for use
only in treatment-experienced adults who have evidence of HIV
replication despite ongoing antiretroviral therapy.
In phase 3 clinical trials involving heavily pretreated patients
with documented multidrug-resistant HIV-1, inclusion of enfuvirtide
(90 mg subcutaneously twice daily) in combination with an optimized
background regimen enhanced the fraction of patients with
undetectable (<50 copies/mL) plasma HIV-1 RNA concentrations
after 24 weeks of treatment (~16% on enfuvirtide versus ~6% without)
(Dando and Perry, 2003). Treatment response is more likely in
patients with at least two other active drugs in the regimen, based
on history and HIV genotype. Given the cost, inconvenience, and
cutaneous toxicity of this drug, enfuvirtide generally is reserved for
patients who have failed all other feasible antiretroviral regimens.
INTEGRASE INHIBITORS
Chromosomal integration is a defining characteristic of
retrovirus life cycles and allows viral DNA to remain in
the host cell nucleus for a prolonged period of inactivity
or latency (Figure 59–1). Because human DNA is
not known to undergo excision and reintegration, this is
an excellent target for antiviral intervention. The first
approved HIV integrase inhibitor, raltegravir, was
licensed in 2007. It prevents the formation of covalent
bonds between host and viral DNA—a process known
as strand transfer—presumably by interfering with
essential divalent cations in the enzyme’s catalytic core
(Hicks and Gulick, 2009; Figure 59–8).
Raltegravir
Chemistry and Mechanism of Action. Raltegravir
blocks the catalytic activity of the HIV-encoded integrase,
thus preventing integration of virus DNA into the
host chromosome (Figure 59–8).
Raltegravir has potent activity against both HIV-1
and HIV-2, with an in vitro IC 95
range of 6-30 nM
(Hicks and Gulick, 2009). Raltegravir retains activity
against viruses that have become resistant to antiretroviral
agents of other classes because of its unique mechanism
of action.
The two major raltegravir resistance pathways involve primary
mutations Q184R/H/K, or N155H in the integrase gene. Either
mutation can confer 25- to 50-fold changes in drug sensitivity in
H 3 C
Raltegravir
N
O
N
O
O
H 3 C
N
H
N
N
H 3 C CH 3
OH
H
N
O
F
Proviral DNA
Raltegravir binds to HIV integrase,
prevents DNA strand transfer.
Raltegravir
Raltegravir
Host
chromosomal
DNA
HIV integrase binds to
proviral 3 LTR’s
Figure 59–8. Mechanism of action of the HIV integrase inhibitor raltegravir.
Host
chromosomal
DNA