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

1618 ≥41% of patients, and reductions in hepatic inflammation in >50%
of patients (Dienstag et al., 1999; Lai et al., 2002). Seroconversion
with antibody to HbeAg occurs in <20% of recipients at 1 year. In
children 2-17 years of age, lamivudine (3 mg/kg/day to a maximum
of 100 mg/day for 1 year) is associated with normalization of aminotransferase
levels in about one-half and seroconversion to anti-Hbe
in about one-fifth of cases (Jonas et al., 2002). In those without emergence
of resistant variants, prolonged therapy is associated with sustained
suppression of HBV DNA, continued histological
improvement, and an increased proportion of patients experiencing
a virological response (loss of HbeAg and undetectable HBV DNA).
Prolonged therapy is associated with an approximate halving of the
risk of clinical progression and development of hepatocellular carcinoma
in those with advanced fibrosis or cirrhosis (Liaw et al.,
2004). However, the frequency of lamivudine-resistant variants
increases progressively with continued drug administration, reaching
67% after 4 years of treatment (Liaw et al., 2004). The risk of resistance
development is higher after transplantation and in HIV/HBV
co-infected patients.
Combined use of IFN or pegIFN alfa-2A with lamivudine has
not improved responses in HBeAg-positive patients consistently. The
addition of lamivudine to pegINF alfa-2A for 1 year of therapy does
not improve post-treatment response rates in HBeAg-negative
patients (Marcellin et al., 2004). In HIV and HBV co-infections,
higher lamivudine doses are associated with antiviral effects and
uncommonly anti-HBe seroconversion. Administration of lamivudine
before and after liver transplantation may suppress recurrent
HBV infection.
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
Telbivudine
Chemistry and Antiviral Activity. Telbivudine (Figure
58–6) is a synthetic thymidine nucleoside analog with
activity against HBV DNA polymerase.
Mechanisms of Action and Resistance. Telbivudine is
phosphorylated by cellular kinases to the active triphosphate
form, which has a t 1/2
of 14 hours. Telbivudine 5′-
triphosphate inhibits HBV DNA polymerase (reverse
transcriptase) by competing with the natural substrate,
thymidine 5′-triphosphate. Incorporation of telbivudine
5′-triphosphate into viral DNA causes chain termination.
Telbivudine 5′-triphosphate at concentrations up
to 100 μM did not inhibit human cellular DNA polymerases
α, β, or γ.
In cell-based assays, lamivudine-resistant HBV strains expressing
either the M204I substitution or the L180M/M204V double substitution
had ≥1000-fold reduced susceptibility. Telbivudine retained
wild-type phenotypic activity against the lamivudine resistance–
associated substitution M204V alone. HBV encoding the adefovir
mutation A181V showed 3- to 5-fold reduced susceptibility, but
N236T remained susceptible. The A181S and A181T substitutions
conferred 2.7- and 3.5-fold reductions in susceptibility to telbivudine,
respectively. The A181T substitution is associated with decreased clinical
response in patients with HBV treated with adefovir and entecavir
(Hadziyannis and Vassilopoulos, 2008).
In a cell culture model, the EC 50
for inhibition of viral DNA
synthesis by telbivudine was 0.2 μM. The anti-HBV activity of telbivudine
is additive with that of adefovir in cell culture, and it is not
antagonized by the HIV-1 nucleoside analogs didanosine and stavudine
(Hadziyannis and Vassilopoulos, 2008).
Absorption, Distribution, and Elimination. At 600 mg once daily,
steady-state peak concentrations are ~3.7 μg/mL at a median of
2 hours post-dose. Steady state is achieved after ~5-7 days of oncedaily
administration with ~1.5-fold accumulation. In vitro protein
binding is low (3.3%) and telbivudine is widely distributed into tissues.
Telbivudine concentrations decline biexponentially with an
elimination t 1/2
of 40-49 hours. The drug is eliminated unchanged in
the urine.. Patients with moderate-to-severe renal dysfunction and
those undergoing hemodialysis require dose adjustments.
Untoward Effects. Telbivudine is generally well tolerated and safe.
The most common adverse events resulting in telbivudine discontinuation
included increased creatine kinase, nausea, diarrhea, fatigue,
myalgia, and myopathy. Elevations of creatine kinase activity, mostly
asymptomatic grade 3-4, were more common in telbivudine-treated
patients after 2 years of therapy than with lamivudine.
Therapeutic Uses. Similar to other oral HBV agents, telbivudine is
indicated for the treatment of chronic HBV in adult patients with
evidence of viral replication and either evidence of persistent elevations
in serum aminotransferases (ALT or AST) or histologically
active disease.
The recommended dose is 600 mg orally once daily without
regard to food. An oral solution is also available. This dose is based
on pharmacodynamic analyses showing a relationship between telbivudine
dose and changes in HBV DNA from baseline to week 4
(Lai et al., 2004). The dose producing the maximum effect was
between 400 and 800 mg/day. The drug has not been studied in
patients with HBV/HIV co-infection. Telbivudine resistance is substantial
(25%) after 2 years of treatment and higher than observed
with other oral anti-HBV agents (Dienstag, 2009; Hadziyannis and
Vassilopoulos, 2008). Cross-resistance and treatment-emergent
resistance have limited the use of telbivudine for patients with
chronic HBV, compared to alternative agents.
Tenofovir
Tenofovir is a nucleotide analog with activity against
both HIV-1 and HBV (Figure 58–6). It is administered
orally as the disoproxil prodrug. Chemistry, pharmacokinetic
properties, untoward effects, precautions, and
interactions for this drug are covered in more detail in
Chapter 59.
In in vitro cell cultures, the EC 50
for tenofovir against HBV
ranged from 0.14 to 1.5 μM, with cytotoxicity concentrations
>100 μM. No antagonistic activity was observed when combined
with other oral anti-HBV agents. In cell-based assays, mutant
HBV (V173L, L180M, and M204I/V) associated with resistance
to lamivudine and telbivudine showed a susceptibility to tenofovir
of 0.7-3.4 times that of wild-type virus. Overall, tenofovir has a
favorable resistance profile and has been effective in treating
lamivudine-resistant HBV (Dienstag, 2009).