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

Table 59–3
Pharmacokinetic Properties of Non-nucleoside Reverse Transcriptase Inhibitors a
PARAMETER NEVIRAPINE b EFAVIRENZ b ETRAVIRINE
Oral bioavailability, % 90-93 50 NR
Effect of meals on AUC i a17-28% a33-102%
Plasma t 1/2
, elim, h 25-30 40-55 41
Plasma protein binding, % 60 99 99.9
Metabolism CYP3A4 > CYP2B6 > CYP3A4, 2C9,
CYP2B6 CYP3A4 2C19, UGT
Renal excretion of parent drug, % <3 <3 1%
Autoinduction of metabolism Yes Yes NR
Inhibition of CYP3A No Yes No
ABBREVIATIONS: AUC, area under plasma concentration–time curve; t 1/2
, elim, half-life of elimination; a, increase; b, decrease; i, no effect; NR, not
reported; CYP, cytochrome P450; UGT, UDP-glucuronosyltransferase.
a
Reported mean values in adults with normal renal and hepatic function. b Values at steady state after multiple oral doses.
for treatment-naive patients in recognition of its convenience, tolerability,
and potency. Rashes occur frequently with all NNRTIs, usually
during the first 4 weeks of therapy. These generally are mild and
self-limited, although rare cases of potentially fatal Stevens-Johnson
syndrome have been reported with nevirapine, efavirenz, and
etravirine. Fat accumulation can be seen after long-term use of
NNRTIs (Calmy et al., 2009), and fatal hepatitis has been associated
with nevirapine use.
Nevirapine
Chemistry and Antiviral Activity. Nevirapine is a
dipyridodiazepinone NNRTI with potent activity against
HIV-1 (Figure 59–4).
The in vitro IC 50
of this drug ranges from 10 to 100 nM. Like
other compounds in this class, nevirapine does not have significant
activity against HIV-2 or other retroviruses (Sheran, 2005).
Mechanisms of Action and Resistance. A single mutation
at either codon 103 or codon 181 of reverse transcriptase
decreases susceptibility by more than two
orders of magnitude (Kuritzkes, 2004). Nevirapine
resistance is also associated with mutations at codons
100, 106, 108, 188, and 190, but either the K103N or
the Y181C mutation is sufficient to produce high-level
resistance and clinical treatment failure (Eshleman et al.,
2004). Cross-resistance extends to efavirenz and
delavirdine, and any patient who fails treatment with
this NNRTI should not be treated with those drugs.
Absorption, Distribution, and Elimination. Nevirapine is well
absorbed, and its bioavailability is not altered by food or antacids. The
drug readily crosses the placenta and has been found in breast milk, a
feature that has encouraged use of nevirapine for prevention of motherto-child
transmission of HIV (Mirochnick et al., 1998).
Nevirapine is eliminated mainly by oxidative metabolism
involving CYP3A4 and CYP2B6. Less than 3% of the parent drug
is eliminated unchanged in the urine. Nevirapine has a long elimination
t 1/2
of 25-30 hours at steady state, but t 1/2
may be longer in some
individuals, especially those of African descent (Sheran, 2005). The
drug is a moderate inducer of CYPs, including CYP3A4; thus the
drug induces its own metabolism, which decreases the t 1/2
from 45
hours following the first dose to 25-30 hours after 2 weeks. To compensate
for this, it is recommended that the drug be initiated at a
dose of 200 mg once daily for 14 days, with the dose then increased
to 200 mg twice daily if no adverse reactions have occurred. Clinical
studies of nevirapine have investigated once-daily use, but this dosing
regimen is not approved.
Untoward Effects. The most frequent adverse event associated with
nevirapine is rash, which occurs in ~16% of patients. Mild macular
or papular eruptions commonly involve the trunk, face, and extremities
and generally occur within the first 6 weeks of therapy. Pruritus
is also common. In most patients the rash resolves with continued
administration of drug. Up to 7% of patients discontinue therapy
owing to rash; administration of glucocorticoids may cause a more
severe rash. Life-threatening Stevens-Johnson syndrome is rare but
occurs in up to 0.3% of recipients (Sheran, 2005).
Elevated hepatic transaminases occur in up to 14% of
patients. Clinical hepatitis occurs in up to 1% of patients. Severe and
fatal hepatitis has been associated with nevirapine use, and this may
be more common in women with CD4 counts >250 cells/mm 3 , especially
during pregnancy (Sheran, 2005). Other reported side effects
include fever, fatigue, headache, somnolence, and nausea.
Precautions and Interactions. Because nevirapine induces
CYP3A4, this drug may lower plasma concentrations of co-administered
CYP3A4 substrates. Methadone withdrawal has been
reported in patients receiving nevirapine, presumably as a consequence
of enhanced methadone clearance. Plasma ethinyl estradiol
and norethindrone concentrations decrease by 20% with nevirapine,
and alternative methods of birth control are advised.