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

1644 effective in patients who have failed previous antiretroviral
therapy not containing an NNRTI (Sheran, 2005).
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
Efavirenz is used widely in the developed world because of
its convenience, effectiveness, and long-term tolerability. Especially
popular is the once-daily single pill co-formulation of efavirenz, tenofovir,
and emtrictabine (ATRIPLA). To date, no antiretroviral regimen
has produced better long-term treatment responses than efavirenzcontaining
regimens in randomized prospective clinical trials. As a
result, efavirenz plus two nucleoside reverse transcriptase inhibitors
remains a preferred regimen for treatment-naive patients. Generic
versions of efavirenz are increasingly used in treatment regimens in
resource-poor countries because of this drug’s better toxicity profile
compared to nevirapine. Efavirenz can be safely combined with
rifampin and is useful in patients also being treated for tuberculosis.
Efavirenz is approved for adult and pediatric patients ≥3 years
of age and weighing at least 10 kg. Efavirenz is only available as
tablets and capsules; pediatric dosing is based on weight range.
Etravirine
Chemistry and Antiviral Activity. Etravirine is a
diarylpyrimidine NNRTI that is active against HIV-1
(Figure 59–4). The IC 50
for HIV-1 in various in vitro
assays ranges from 1 to 5 nM, but like other NNRTIs,
etravirine has no activity against HIV-2 (Deeks and
Keating, 2008).
Mechanisms of Action and Resistance. Etravirine is
unique in its ability to inhibit reverse transcriptase that
is resistant to other available NNRTIs. Specifically,
activity of the drug is not affected by the K103N,
Y181C, or Y188L mutations or the K103N/Y181C
double mutations that confer high-level resistance to
efavirenz, nevirapine, and delavirdine.
Etravirine appears to have conformational and positional flexibility
in the NNRTI binding pocket that allow it to inhibit the function
of the HIV-1 reverse transcriptase in the presence of common
NNRTI resistance mutations (Deeks and Keating, 2008). Clinically
significant drug resistance and treatment failure require the presence
of multiple mutations, including V90I, A98G, L100I, K101E/P,
V106I, V179D/F, Y181C/I/V, and G190A/S. Best response to an
etravirine-containing regimen is seen in patients harboring three or
fewer resistance mutations, although likelihood of virologic benefit
decreases with each additional mutation. One limitation of etravirine
resistance data is that most information comes from patients also
receiving darunavir, and few resistance and response data are available
for other regimens (Fulco and McNicholl, 2009).
Absorption, Distribution, and Elimination. Etravirine is absorbed
rapidly after oral administration with peak concentrations occurring
2.5-4 hours after dosing. Food increases the etravirine AUC by 50%
(Deeks and Keating, 2008), and it is therefore recommended that the
drug be administered with food. Methyl- and dimethyl-hydroxylated
metabolites are produced in the liver primarily by CYPs 3A4, 2C9,
and 2C19, accounting for most of the elimination of this drug. No
unchanged drug is detected in the urine. The terminal elimination t 1/2
is ~41 hours; twice-daily dosing of this drug is the historical consequence
of enormous pill burdens from older formulations that are
no longer in use, and it is likely that the drug could be given once daily
(Deeks and Keating, 2008). Etravirine is 99% bound to plasma proteins,
mainly to albumin and α 1
-acid glycoprotein.
Untoward Effects. In randomized placebo-controlled trials combining
etravirine with darunavir in treatment-experienced patients, the
only side effect occurring more commonly with etravirine than with
placebo was rash (17% versus 9%), usually occurring within a few
weeks of starting therapy and resolving within 1-3 weeks. Overall,
2% of patients in these trials discontinued etravirine because of rash.
Severe rash including Stevens-Johnson syndrome and toxic epidermal
necrolysis have been reported. Etravirine was not associated with
more neuropsychiatric or hepatic adverse effects than placebo (Deeks
and Keating, 2008).
Precautions and Interactions. Etravirine is an inducer of CYP3A4
and glucuronosyl transferases, and an inhibitor of CYPs 2C9 and
2C19, and can therefore be involved in a number of clinically significant
pharmacokinetic drug interactions.
Etravirine can be combined with darunavir/ritonavir,
lopinavir/ritonavir, and saquinavir/ritonavir without the need for dose
adjustments. The dose of maraviroc should be doubled to 600 mg
twice daily when these two drugs are combined. Etravirine should not
be administered with tipranavir/ritonavir, fosamprenavir/ritonavir, or
atazanavir/ritonavir in the absence of better data to guide dosing.
Etravirine should not be combined with efavirenz, nevirapine, or
delavirdine. Unlike other NNRTIs, etravirine does not appear to alter
the clearance of methadone (Fulco and McNicholl, 2009).
Therapeutic Use. Etravirine (INTELENCE) is approved for
use only in treatment-experienced HIV-infected adults.
NNRTI-experienced patients should not receive
etravirine plus NRTIs alone. Etravirine has not yet been
approved for pediatric use.
In a pooled analysis of >1200 treatment-experienced patients
taking darunavir/ritonavir, 61% of patients randomized to etravirine
achieved a plasma HIV RNA <50 copies/mL at 48 weeks compared
to 40% on placebo (p < 0.0001). Etravirine-treated patients also had
a moderately better mean CD4 cell count increase at week 48
(98 vs. 73 cells/mm 3 ). Week 48 virologic responses were dependent
on the number of baseline etravirine-resistance mutations, with a differential
versus placebo of 75% versus 44% if no mutations were
present, falling to 25% versus 17% if four or more were present
(Fulco and McNicholl, 2009). In small studies, virologic response
with etravirine was poor unless the regimen contained at least one
other active antiretroviral.
Delavirdine
Delavirdine is a bisheteroarylpiperazine NNRTI that selectively
inhibits HIV-1 (Figure 59–4). The in vitro IC 50
ranges from 6 to
30 nM for laboratory HIV-1 isolates to 1 to 700 nM for clinical isolates
(Scott and Perry, 2000). Delavirdine (RESCRIPTOR) is no longer
used widely because of its short t 1/2
and requirement for thrice-daily
dosing.
Delavirdine does not have significant activity against HIV-2
or other retroviruses. Delavirdine shares resistance mutations with