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

Entecavir triphosphate is a weak inhibitor of cellular DNA
polymerases α, β, and δ and mitochondrial DNA polymerase γ. The
inhibitory concentration against HBV is 0.004 μM in transfected
cells and ranges from 0.01 to 0.059 μM against lamivudine-resistant
(L180M, M204V) HBV. Eight- to 30-fold reductions in entecavir
susceptibility were observed for lamivudine-resistant strains in cellbased
assays (Scott and Keating, 2009).
Entecavir selected for an M184I substitution in HIV reverse
transcriptase at μM concentrations in cell culture, and HIV variants
containing the M184V substitution showed loss of susceptibility to
entecavir. In patients, entecavir decreased HIV-1 RNA in three persons
with HIV-1 and HBV co-infection and led to HIV-1 variants
with the M184V lamivudine-resistant mutation in one subject
(McMahon et al., 2007). Lamivudine and telbivudine resistance confers
decreased susceptibility to entecavir. In patients with preexisting
lamivudine resistance, entecavir resistance emerged in 7% and
43% after 1 and 4 years, respectively (Dienstag, 2009).
Absorption, Distribution, and Elimination. Following multiple
daily doses ranging from 0.1 to 1.0 mg, C max
and area under the
concentration-time curve (AUC) at steady-state increased in proportion
to dose. Time to peak occurs in 0.5-1.5 hours. Steady-state is
reached after 6-10 days of once daily dosing. The tablet and oral
solution can be used interchangeably. Administration with food
decreases C max
by 44-46% and AUC by 18-20%; thus entecavir
should be administered on an empty stomach.
Entecavir is extensively distributed in tissues and is 13%
bound to serum proteins. It is primarily eliminated unchanged in the
kidney. Renal clearance is independent of dose and ranges from 360
to 471 mL/minute, suggesting that entecavir undergoes both
glomerular filtration and net tubular secretion. Entecavir exhibits
biphasic elimination, with a terminal t 1/2
of 128-149 hours; the active
triphosphate has an elimination t 1/2
of 15 hours. Dose reductions are
needed for patients with Cl Cr
<50 mL/minute, typically by extension
of the dosing interval (Scott and Keating, 2009).
Untoward Effects. Severe acute exacerbations of hepatitis B have
been reported in patients who have discontinued anti-HBV therapy,
including entecavir. Hepatic function should be monitored closely
with both clinical and laboratory follow-up for at least several
months in patients who discontinue anti-HBV therapy. There is a
potential for development of resistance to nucleoside reverse transcriptase
inhibitors in HBV/HIV co-infection especially if HIV is
not being treated. Lactic acidosis and severe hepatomegaly with
steatosis, including fatal cases, have been reported, mostly in women
with some antiretroviral nucleoside analogs (Chapter 59), but not
with entecavir. Other common adverse reactions include headache,
fatigue, dizziness, and nausea (Scott and Keating, 2009).
Therapeutic Uses. Entecavir is indicated for the treatment
of chronic HBV infection in adults with active
viral replication and either evidence of persistent elevations
in serum aminotransferases or histologically
active disease.
The recommended dose for nucleoside-treatment-naive adults
(>16 years of age) is 0.5 mg once daily. For patients with lamivudine
or telbivudine resistance, the dose is 1 mg once daily. Entecavir is
superior to lamivudine in the degree of suppression and associated
with a more frequent fall of HBV DNA to undetectable levels
(Dienstag, 2009). Durability of HBeAg responses is comparable to
other oral agents. Entecavir had negligible resistance (≤1%) for up
to 4 years and is active against adefovir-resistant HBV.
Lamivudine
Chemistry and Antiviral Activity. Lamivudine, the (–)-
enantiomer of 2′,3′-dideoxy-3′-thiacytidine, is a nucleoside
analog that inhibits HIV reverse transcriptase and
HBV DNA polymerase (Figure 58–6). Its use as an
antiretroviral agent is discussed in Chapter 59.
It inhibits HBV replication in vitro by 50% at
concentrations of 4-7 ng/mL with negligible cellular
cytotoxicity. Cellular enzymes convert lamivudine to
the triphosphate, which competitively inhibits HBV
DNA polymerase and causes chain termination.
Mechanisms of Action and Resistance. Lamivudine
triphosphate is a potent inhibitor of the DNA polymerase/reverse
transcriptase of HBV; the intracellular
t 1/2
of the triphosphate averages 17-19 hours in HBVinfected
cells, so once-daily dosing is possible.
Oral lamivudine is active in animal models of hepadnavirus
infection. Lamivudine shows enhanced antiviral activity in combination
with adefovir or penciclovir against hepadnaviruses. Point mutations
in the YMDD motif of HBV DNA polymerase result in a 40-
to 104-fold reduction in in vitro susceptibility (Ono et al., 2001).
Lamivudine resistance confers cross-resistance to related agents such
as emtricitabine and the investigational agent, clevudine, and is often
associated with an additional non-YMDD mutation that confers
cross-resistance to famciclovir. Lamivudine-resistant HBV retains
susceptibility to adefovir, tenofovir, and partially to entecavir (Ono
et al., 2001). Viruses bearing YMDD mutations are less replication
competent in vitro than wild-type HBV. However, lamivudine resistance
is associated with elevated HBV DNA levels, decreased likelihood
of HbeAg loss or seroconversion, hepatitis exacerbations, and
progressive fibrosis and graft loss in transplant recipients (Dienstag
et al., 2003; Lai et al., 2002).
Absorption, Distribution, and Elimination. The pharmacokinetic
properties of lamivudine are described in detail in Chapter 59. In HBVinfected
children, doses of 3 mg/kg/day provide plasma exposure
and trough plasma levels comparable with those in adults receiving
100 mg daily (Sokal et al., 2000). Dose reductions are indicated for
moderate renal insufficiency (creatinine clearance <50 mL/minute).
Trimethoprim decreases the renal clearance of lamivudine.
Untoward Effects. At the doses used for chronic HBV infection,
lamivudine generally has been well tolerated. Aminotransferase rises
after therapy occur more often in lamivudine recipients, and flares in
post-treatment aminotransferase elevations (>500 IU/mL) occur in
~15% of patients after cessation.
Therapeutic Uses. Lamivudine is approved for the treatment of
chronic HBV hepatitis in adults and children.
In adults, doses of 100 mg/day for 1 year cause suppression
of HBV DNA levels, normalization of aminotransferase levels in
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CHAPTER 58
ANTIVIRAL AGENTS (NONRETROVIRAL)