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

1616 anti-HBV nucleosides show enhanced antihepadnavirus
activity in vitro (Delaney et al., 2004), and trials of dual
therapy are in progress.
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
Mechanisms of Action and Resistance. Adefovir dipivoxil
enters cells and is deesterified to adefovir.
Adefovir is converted by cellular enzymes to the
diphosphate, which acts as a competitive inhibitor of
viral DNA polymerases and reverse transcriptases with
respect to deoxyadenosine triphosphate and also serves
as a chain terminator of viral DNA synthesis (Cundy,
1999). Its selectivity relates to a higher affinity for HBV
DNA polymerase compared with cellular polymerases.
The intracellular t 1/2
of the diphosphate is prolonged,
ranging from 5 to 18 hours, so once-daily dosing
is feasible. Adefovir resistance has been detected in
a small proportion (~4%) of chronically infected HBV
patients during 3 years of treatment. Such variants have
unique point mutations in the HBV polymerase but
retain susceptibility to lamivudine. The consequences
of the emergence of resistance remain to be determined.
Absorption, Distribution, and Elimination. The parent compound
has low oral bioavailability (<12%), whereas the dipivoxil prodrug
is absorbed rapidly and hydrolyzed by esterases in the intestine and
blood to adefovir with liberation of pivalic acid, providing a bioavailability
~30-60%. After 10-mg doses of the pro-drug, peak serum
concentrations of adefovir average 0.02 μg/mL, and the pro-drug is
not detectable. Food does not affect bioavailability. Adefovir is scantily
protein bound (<5%) and has a volume of distribution similar to
body water (~0.4 L/kg).
Adefovir is eliminated unchanged by renal excretion through
a combination of glomerular filtration and tubular secretion. After
oral administration of adefovir dipivoxil, ~30-45% of the dose is
recovered within 24 hours; the serum t 1/2
of elimination is 5-7.5
hours. Dose reductions are recommended for Cl Cr
values <50
mL/minute. Adefovir is removed by hemodialysis, but the effects of
peritoneal dialysis or severe hepatic insufficiency on pharmacokinetics
are unknown.
Pivalic acid is a product of adefovir dipivoxil metabolism that
can cause reduced free carnitine levels. Although L-carnitine has
been given in some investigational HIV studies of adefovir, supplementation
generally is not recommended at the doses used in chronic
HBV infection.
Untoward Effects. Adefovir dipivoxil causes dose-related nephrotoxicity
and tubular dysfunction, manifested by azotemia and
hypophosphatemia, acidosis, glycosuria, and proteinuria that usually
are reversible months after discontinuation. The lower dose
(10 mg/day) used in chronic HBV infection patients has been associated
with few adverse events (e.g., headache, abdominal discomfort,
diarrhea, and asthenia) and negligible renal toxicity compared
with a 3-fold higher dose (Hadziyannis et al., 2003; Marcellin et al.,
2003). Adverse events lead to premature discontinuation in ~2% of
patients. After 2 years of dosing, the risk of serum creatinine levels
rising above 0.5 mg/dL is ~2% but is higher in those with preexisting
renal insufficiency. Acute, sometimes severe exacerbations of
hepatitis can occur in patients stopping adefovir or other anti-HBV
therapies. Close monitoring is necessary, and resumption of antiviral
therapy may be required in some patients.
No clinically important drug interactions have been recognized
to date, although drugs that reduce renal function or compete
for active tubular secretion could decrease adefovir clearance.
Ibuprofen increases adefovir exposure modestly. An increased risk of
lactic acidosis and steatosis may exist when adefovir is used in conjunction
with nucleoside analogs or other antiretroviral agents.
Adefovir is transported efficiently into tubular epithelium by a
probenecid-sensitive organic anion transporter (hOAT1).
Adefovir is genotoxic, and high doses cause hepatotoxicity,
lymphoid toxicity, and renal tubular nephropathy in animals. The
diphosphate’s inhibitory effects on renal adenylyl cyclase may contribute
to nephrotoxicity. Adefovir dipivoxil is not associated with
reproductive toxicity, although high intravenous doses of adefovir
cause maternal and embryotoxicity with fetal malformations in rats
(pregnancy Category C).
Therapeutic Uses. Adefovir dipivoxil is approved for treatment of
chronic HBV infections.
In patients with HBV e-antigen (HbeAg)–positive chronic
hepatitis B, adefovir dipivoxil (10 mg/day) reduces serum HBV
DNA levels by 99% and, in about one-half of patients, improves
hepatic histology and normalization of aminotransferase levels by
48 weeks (Marcellin et al., 2003). Continued therapy is associated
with increasing frequencies of aminotransferase normalization and
HbeAg seroconversion (De Clercq, 2003). In patients with HbeAgnegative
chronic HBV, adefovir is associated with similar biochemical
and histological benefits (Hadziyannis et al., 2003). Regression
of cirrhosis may occur in some patients.
In patients with lamivudine-resistant HBV infections, adefovir
dipivoxil monotherapy results in sustained reductions in serum
HBV DNA levels, but lamivudine alone or added to adefovir is not
beneficial (Peters et al., 2004). In patients with dual HIV and
lamivudine-resistant HBV infections, adefovir dipivoxil (10
mg/day) causes significant HBV DNA level reductions (Benhamou
et al., 2001), and it also has been used successfully in patients with
lamivudine-resistant HBV infections both before and following
liver transplantation. The optimal duration of treatment in different
populations, possible long-term effects on HBV complications, and
combined use with other anti-HBV agents are under study.
Entecavir
Chemistry and Antiviral Activity. Entecavir is a guanosine
nucleoside analog with selective activity against
HBV polymerase (Figure 58–6).
Mechanisms of Action and Resistance. Entecavir
requires intracellular phosphorylation. Entecavir
triphosphate competes with endogenous deoxyguanosine
triphosphate and inhibits all three activities of the
HBV polymerase (reverse transcriptase):
• base priming
• reverse transcription of the negative strand from the
pregenomic messenger RNA
• synthesis of the positive strand of HBV DNA