This article reviews the pharmacology/pharmacokinetics and therapeutic efficacy of
entecavir, which was approved on March 29, 2005, for the management of adult patients with
chronic hepatitis B virus (HBV)
infection who have active viral replication and/or elevations in liver
transaminases or signs of active
liver disease on histologic examination. Potential drug interactions and adverse events associated with the use of
entecavir are also reviewed.
METHODS: Relevant literature was identified through searches of MEDLINE (1996-July 2005) and BIOSIS (1993-July 2005). Search terms included, but were not limited to,
entecavir,
BMS-200475,
hepatitis B, pharmacology, pharmacokinetics, adverse events, and
therapeutic use. Further publications were identified from the reference lists of the identified articles and through correspondence with the manufacturer of
entecavir.
RESULTS:
Entecavir is highly selective for the HBV and inhibits all 3 steps of viral replication. Results of early studies indicated a 6% resistance potential after 48 weeks of
therapy, although the potential may be higher in patients who harbor
lamivudine-resistant mutants. The approved dosage in treatment-naive patients is 0.5 mg/d p.o., administered on an empty stomach; in patients who have failed
lamivudine therapy or are known to harbor
lamivudine-resistant mutants, the approved dosage is 1.0 mg/d p.o.. The oral
tablet and
solution can be used interchangeably.
Entecavir is well absorbed orally, achieving a dose-related Cmax between 0.6 and 1.5 hours after administration. It is metabolized to a small extent and is not a substrate for the
cytochrome P450 enzyme system. The mean elimination t(1/2) ranges from 77 to 149 hours in patients with normal kidney function.
Entecavir is eliminated primarily in the urine via glomerular filtration and tubular secretion (62%-73%). No dose adjustment appears to be necessary in patients with moderate to severe
liver disease alone. The potential for drug interactions with
entecavir appears to be minimal, although medications that inhibit tubular secretion of drugs (eg,
probenecid) may be expected to prolong serum concentrations of
entecavir. One of the Phase III studies of
entecavir found statistically significant benefits compared with
lamivudine in terms of improvements in liver histology after 48 weeks of
therapy (72% vs 62%, respectively; P<0.009), the proportions of patients with undetectable HBV
DNA titers on branched
DNA signal amplification assay after 48 weeks of
therapy (91% vs 65%; P<0.001), and the proportion with undetectable HBV
DNA on polymerase chain reaction (PCR) assay after 48 weeks of
therapy (69% vs 38%; P<0.001). In another Phase III study, patients who had failed to respond to
lamivudine therapy responded to
entecavir: after 48 weeks of
therapy, significant differences between
entecavir and
lamivudine were seen in histologic improvement (55% vs 28%; P<0.001) and the proportion of patients with undetectable HBV
DNA on PCR assay (21% vs 1%; P<0.001). Adverse events associated with
entecavir therapy were similar in character, severity, and incidence to those associated with placebo or
lamivudine therapy. The most common adverse events in clinical trials of
entecavir were
headache (17%-23% of patients),
upper respiratory tract infection (18%-20%),
cough (12%-15%),
nasopharyngitis (9%-14%),
fatigue (10%-13%),
dizziness (9%), upper
abdominal pain (9%-10%), and
nausea (6%-8%).
CONCLUSIONS: