There are approximately 400 million people worldwide
with chronic hepatitis B virus (HBV) infection, about onethird
of whom have potentially progressive and life-threatening
liver disease associated with the infection. Chronic
hepatitis B infection can lead to cirrhosis, liver failure and hepatocellular carcinoma. Globally, HBV infection accounts
for over one million deaths annually. At present, lamivudine
and adefovir dipivoxil are the only approved nucleoside/
nucleotide analogs for the treatment of HBV infection. However,
resistance to lamivudine is now recognized in 16 to
32% of HBV-infected patients after the first year of monotherapy
and about 50% of patients after two years.
With adefovir treatment, the resistance rate is much lower, at
about 2.5% after two years of therapy. Experience in treating
chronic HIV infections has proven the advantage of therapy
with a combination of antiviral compounds. Similarly for
HBV, there is a clear need for additional antiviral compounds.
Several promising candidates are currently in clinical
development. Idenix (then known as Novirio) discovered
that the known beta-L-nucleosides, L-dA, L-dC (torcitabine)
and L-dT (telbivudine), have highly specific activity against
HBV. These L-nucleosides are essentially without activity
against any of the other viruses tested and are similarly
without effect in cell culture and in vivo toxicological tests.
However, they are phosphorylated within human cells to
their triphosphates which inhibit the HBV DNA polymerase,but not human polymerases. Of these three compounds,
telbivudine was the only one to combine reasonable
oral bioavailability with good anti-HBV activity and so was
progressed to development jointly with Novartis with the
highest priority.
使用
Antiviral (treatment of
hepatitis B infection).
獲得抵抗性
After 1 year resistance occurred in 7–20% of patients on telbivudine
depending upon past exposure to other drugs used
in the treatment of hepatitis B and the type of infection.
Development of resistance was less frequent in those receiving
telbivudine than in those receiving lamivudine.
応用例（製薬）
A synthetic thymidine nucleoside analog formulated for oral
use in the treatment of chronic hepatitis B infection.
薬物動態学
Oral absorption： 100%
Cmax 600 mg/kg oral： 3.7 μg/mL
Volume of distribution： In excess of body water
Plasma protein binding：3.3%
It is eliminated renally, necessitating dose adjustment in
patients with renal insufficiency.
It should not be administered with pegylated interferon
because of an increased risk of neuropathy.
臨床応用
Treatment of chronic hepatitis B in patients >16 years of age
副作用
Adverse effects are similar to those of lamivudine and include
upper respiratory tract infection, headache, fatigue and gastrointestinal
upset. Myopathy and peripheral neuropathy are
rare but have been observed in some patients several weeks
into the course with associated rise in serum creatine kinase
levels. Acute exacerbations of hepatitis have been observed on
discontinuation of therapy. Lactic acidosis may occur, necessitating
drug discontinuation.
