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

1638 atazanavir increases the tenofovir AUC by 25%. These interactions
are most likely mediated by tenofovir’s interaction with drug
transport proteins.
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
Therapeutic Use. Tenofovir (VIREAD) is FDA approved
for treating HIV infection in adults in combination with
other antiretroviral agents.
The use of tenofovir in antiretroviral-experienced patients
resulted in a further sustained decrease in HIV plasma RNA concentrations
of 4.5-7.4-fold relative to placebo after 48 weeks of treatment
(Chapman et al., 2003). Several large trials have confirmed the
antiretroviral activity of tenofovir in three-drug regimens with other
agents, including other nucleoside analogs, protease inhibitors, and/or
NNRTIs. In a randomized double-blind comparison trial in which
treatment-naive patients also received lamivudine and efavirenz, tenofovir
300 mg once daily was as effective and less toxic than stavudine
40 mg twice daily (Gallant et al., 2004). Tenofovir is also being investigated
as a component of prophylactic regimens, including in the
prevention of mother-to-child transmission, and it may have advantages
over zidovudine in these settings (Foster et al., 2009).
Tenofovir is also approved for the treatment of chronic hepatitis
B in adults.
Emtricitabine
Chemistry and Antiviral Activity. Emtricitabine is a cytidine
analog chemically related to lamivudine and shares
many of that drug’s pharmacodynamic properties.
Like lamivudine, it has two chiral centers and is manufactured
as the enantiomerically pure (2R,5S)-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine
(FTC) (Figure 59–2).
Emtricitabine is active against HIV-1, HIV-2, and HBV. The IC 50
of
emtricitabine against laboratory strains of HIV-1 ranges from 2 to
530 nM, although, on average, the drug is ~10 times more active in
vitro than lamivudine (Saag, 2006).
Mechanisms of Action and Resistance. Emtricitabine
enters cells by passive diffusion and is phosphorylated
by deoxycytidine kinase and cellular kinases to
its active metabolite, emtricitabine 5′-triphosphate
(Figure 59–3). Like lamivudine, emtricitabine has
low affinity for human DNA polymerases, explaining
its low toxicity to the host.
High-level resistance to emtricitabine occurs with the same
mutations affecting lamivudine (mainly the methionine-to-valine substitution
at codon 184), although these appear to occur less frequently
with emtricitabine. In three studies, M184V/I occurred about half as
frequently with emtricitabine-containing regimens as with lamivudine,
and patients presenting with virologic failure were two to three times
as likely to have wild-type virus at the time of failure as compared
with lamivudine (Saag, 2006). The M184V mutation restores zidovudine
susceptibility to zidovudine-resistant HIV and also partially
restores tenofovir susceptibility to tenofovir-resistant HIV harboring
the K65R mutation (Wainberg et al., 1999). The same K65R mutation
confers resistance to emtricitabine and the other cytidine analog
lamivudine, as well as didanosine, stavudine, and abacavir.
Absorption, Distribution, and Elimination. Emtricitabine is
absorbed rapidly and has an oral bioavailability of 93%. Food reduces
the C max
but does not affect the AUC, and the drug can be taken without
regard to meals. Emtricitabine is not bound significantly to plasma
proteins. Compared with other nucleoside analogs, the drug has a slow
systemic clearance and long elimination t 1/2
of 8-10 hours (Saag, 2006).
In addition, the estimated t 1/2
of the intracellular triphosphate is long,
possibly up to 39 hours, providing the pharmacokinetic rationale for
once-daily dosing. Emtricitabine is excreted primarily unchanged in
the urine, undergoing glomerular filtration and active tubular secretion.
The dose should be reduced in those with estimated creatinine
clearances of <50 mL/minute.
Untoward Effects. Emtricitabine is one of the least toxic antiretroviral
drugs and, like its chemical relative lamivudine, has few significant
adverse effects and no effect on mitochondrial DNA in vitro
(Saag, 2006).
Prolonged exposure has been associated with hyperpigmentation
of the skin, especially in sun-exposed areas. Elevated hepatic
transaminases, hepatitis, and pancreatitis have been reported, but
these have occurred in association with other drugs known to cause
these toxicities. Because emtricitabine also has in vitro activity
against HBV, caution is warranted in using this drug in patients
co-infected with HBV and in regions with high HBV seroprevalence;
discontinuation of lamivudine, which is closely related to
emtricitabine, has been associated with a rebound of HBV replication
and exacerbation of hepatitis.
Precautions and Interactions. Emtricitabine is not metabolized to
a significant extent by CYPs, and it is not susceptible to any known
metabolic drug interactions. The possibility of a pharmacokinetic
interaction involving renal tubular secretion, such as that between
trimethoprim and lamivudine, has not been investigated for emtricitabine;
the drug does not alter the pharmacokinetics of tenofovir.
Therapeutic Use. Emtricitabine (EMTRIVA) is FDAapproved
for treating HIV infection in adults in combination
with other antiretroviral agents. Emtricitabine is
available co-formulated with tenofovir ± efavirenz.
Two small monotherapy trials showed that the maximal
antiviral effect of emtricitabine (mean 1.9 log unit decrease in plasma
HIV RNA concentration) was achieved with a dose of 200 mg/day.
Several large trials have confirmed the antiretroviral activity of
emtricitabine in three-drug regimens with other agents, including
nucleoside or nucleotide analogs, protease inhibitors, and/or
NNRTIs. In two randomized comparison studies, emtricitabine- and
lamivudine-based triple-combination regimens had similar efficacy
(Saag, 2006).
Didanosine
Chemistry and Antiviral Activity. Didanosine (2′,3′-
dideoxyinosine; ddI) is a purine nucleoside analog
active against HIV-1, HIV-2, and other retroviruses
including HTLV-1 (Perry and Noble, 1999). Its IC 50
against HIV-1 ranges from 10 nM in monocytesmacrophage
cells, to 10 μM in lymphoblast cell lines.
Didanosine has been supplanted by less toxic drugs.