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

Therapeutic Use. Nevirapine (VIRAMUNE) is FDA
approved for the treatment of HIV-1 infection in adults
and children in combination with other antiretroviral
agents.
In original monotherapy studies, a rapid fall in plasma HIV
RNA concentrations of ≥99% was followed by a return toward baseline
within 8 weeks because of rapid emergence of resistance (Havlir
et al., 1995; Wei et al., 1995). Nevirapine should never be used as a
single agent or as the sole addition to a failing regimen. Nevirapine
is approved for use in infants and children ≥15 days old, with dosing
based on body surface area.
Single-dose nevirapine has been used commonly in pregnant
HIV-infected women to prevent mother-to-child transmission. A single
oral intrapartum dose of 200 mg nevirapine followed by a single
dose given to the newborn reduced neonatal HIV infection to 13%
compared with 21.5% infection with a more complicated zidovudine
regimen (Sheran, 2005). Although this regimen is very inexpensive
and generally well tolerated, the high prevalence of
nevirapine resistance following the single oral dose (Eshleman et al.,
2004), coupled with the recent recognition of fatal nevirapine hepatitis,
has prompted a reexamination of the role this regimen should
play in the prevention of vertical transmission (Department of Health
and Human Services, 2010).
Efavirenz
Chemistry and Antiviral Activity. Efavirenz is a 1,4-
dihydro-2H-3,1-benzoxazin-2-one NNRTI (Figure 59–4)
with potent activity against HIV-1. The in vitro IC 50
of
this drug ranges from 3 to 9 nM (Sheran, 2005). Like
other compounds in this class, efavirenz does not have
significant activity against HIV-2 or other retroviruses.
Mechanisms of Resistance. The most common
efavirenz resistance mutation seen clinically is at codon
103 of reverse transcriptase (K103N), and this
decreases susceptibility up to ≥100-fold (Kuritzkes,
2004). Additional resistance mutations have been seen
at codons 100, 106, 108, 181, 188, 190, and 225, but
either the K103N or Y181C mutation is sufficient to
produce clinical treatment failure. Cross-resistance
extends to nevirapine and delavirdine.
Absorption, Distribution, and Elimination. Efavirenz is well
absorbed from the GI tract and reaches peak plasma concentrations
within 5 hours. There is diminished absorption of the drug with
increasing doses. Bioavailability (AUC) is increased by 22% with a
high-fat meal.
Efavirenz is >99% bound to plasma proteins and, as a consequence,
has a low CSF-to-plasma ratio of 0.01. The clinical significance
of this low CNS penetration is unclear, especially because the
major toxicities of efavirenz involve the CNS. The drug should be
taken initially on an empty stomach at bedtime to reduce side effects
(Sheran, 2005).
Efavirenz is cleared via oxidative metabolism, mainly by
CYP2B6 and to a lesser extent by CYP3A4. The parent drug is not
excreted renally to a significant degree. Efavirenz is cleared slowly,
with an elimination t 1/2
of 40-55 hours at steady state. This safely
allows once-daily dosing. Clearance is even slower in recipients with
the 516G→T and 983C→T CYP 2B6 genotype (Haas et al., 2009),
a common polymorphism in those of Japanese and African ancestry.
Untoward Effects. The most important adverse effects of efavirenz
involve the CNS. Up to 53% of patients report some CNS or psychiatric
side effects, but <5% discontinue the drug for this reason. CNS
symptoms may occur with the first dose and last for hours; more severe
symptoms may require weeks to resolve. Patients commonly report
dizziness, impaired concentration, dysphoria, vivid or disturbing
dreams, and insomnia. Episodes of frank psychosis (depression, hallucinations,
and/or mania) have been associated with initiating efavirenz.
Fortunately, CNS side effects generally become more tolerable and
resolve within the first 4 weeks of therapy.
Rash occurs frequently with efavirenz, in up to 27% of adult
patients (Sheran, 2005). Rash usually occurs within the first few
weeks of treatment but resolves spontaneously and rarely requires
drug discontinuation. Life-threatening skin eruptions such as
Stevens-Johnson syndrome have been reported during postmarketing
experience with efavirenz but are rare.
Other side effects reported with efavirenz include headache,
increased hepatic transaminases, and elevated serum cholesterol.
False-positive urine screening tests for marijuana metabolites also
can occur depending on the assay used (Sheran, 2005).
Efavirenz is the only antiretroviral drug that is unequivocally
teratogenic in primates. When efavirenz was administered to pregnant
cynomolgus monkeys, 25% of fetuses developed malformations.
In 13 known cases where women were exposed to efavirenz
during the first trimester of pregnancy, fetuses or infants had significant
malformations, mainly of the brain and spinal cord. Women of
childbearing potential therefore should use two methods of birth
control and avoid pregnancy while taking efavirenz.
Precautions and Interactions. Efavirenz is a moderate inducer of
hepatic enzymes, especially CYP3A4, but also a weak to moderate
CYP inhibitor; because of the drug’s long t 1/2
, there is no need to
alter drug dose during the first few weeks of treatment.
Efavirenz decreases concentrations of phenobarbital, phenytoin,
and carbamazepine; the methadone AUC is reduced by 33-66%
at steady state. Rifampin concentrations are unchanged by concurrent
efavirenz, but rifampin may reduce efavirenz concentrations
slightly. Efavirenz reduces the rifabutin AUC by 38% on average.
Efavirenz has a variable effect on HIV protease inhibitors. Indinavir,
saquinavir, and amprenavir concentrations are reduced, but ritonavir
and nelfinavir concentrations are increased. Drugs that induce CYPs
2B6 or 3A4 (e.g., phenobarbital, phenytoin, and carbamazepine)
would be expected to increase the clearance of efavirenz and should
be avoided (Sheran, 2005).
Therapeutic Use. Efavirenz (SUSTIVA) was the first antiretroviral
agent approved by the FDA for once-daily
administration. Initial short-term monotherapy studies
showed substantial decreases in plasma HIV RNA, but
the drug should only be used in combination with other
effective agents and should not be added as the sole new
agent to a failing regimen. Efavirenz has also been
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CHAPTER 59
ANTIRETROVIRAL AGENTS AND TREATMENT OF HIV INFECTION