Adefovir Dipivoxil: Use in Chronic Hepatitis B

liver411

Drugs. 2003;63(20):2215-2234.


Adefovir Dipivoxil: A Review of its Use in Chronic Hepatitis B.

Dando T, Plosker G.

Adis International Limited, Auckland, New Zealand.

Adefovir dipivoxil (Hepsera((R))) is an oral prodrug of the nucleotide
analogue adefovir. It is indicated for the treatment of chronic hepatitis B
in adults.Adefovir dipivoxil 10 mg/day significantly improved histological,
biochemical and virological outcomes in hepatitis B e antigen
(HBeAg)-positive and -negative patients, and serological outcomes in
HBeAg-positive patients. In two trials, the proportion of adefovir dipivoxil
recipients showing histological improvement in the liver was approximately
twice that for placebo recipients.In two trials in patients chronically
infected with lamivudine-resistant hepatitis B virus (HBV), switching to or
adding adefovir dipivoxil was significantly more effective at reducing serum
HBV DNA levels than continuing lamivudine monotherapy. In treatment-naive
patients, 1 year's treatment with adefovir dipivoxil plus lamivudine had
similar efficacy to lamivudine plus placebo; however, lamivudine-resistant
HBV emerged in significantly more patients receiving lamivudine plus
placebo. Adefovir dipivoxil has also shown efficacy in noncomparative trials
in patients with decompensated liver disease, patients co-infected with HIV
and patients pre- or post-liver transplantation. Within 96 weeks of
treatment with adefovir dipivoxil, a resistance-conferring mutation emerged
in viral isolates from 1.6% of patients. In vitro, these isolates remained
sensitive to lamivudine, while lamivudine-resistant HBV isolates remained
sensitive to adefovir dipivoxil.Adefovir dipivoxil 10 mg/day is generally
well tolerated. In a pooled analysis of 48-week data from two trials, there
was no marked difference in adverse events or laboratory abnormalities
between adefovir dipivoxil and placebo recipients. Within 96 weeks of
treatment with adefovir dipivoxil, >1% of patients with adequate renal
function developed an increase in serum creatinine levels of >/=0.5 mg/dL
above baseline. Within 48 weeks of treatment, increases in serum creatinine
levels of >/=0.5 mg/dL above baseline were observed in 13% of pre- and
post-liver transplantation patients who generally had renal insufficiency or
risk factors for renal dysfunction at baseline. Most patients continued
treatment with dosage adjustments.Conclusion: Oral adefovir dipivoxil is
effective and generally well tolerated in HBeAg-positive and -negative
patients chronically infected with wild-type or lamivudine-resistant HBV.
Few resistant HBV mutants have emerged to date. Data from ongoing long-term
studies are awaited with interest. Existing treatment options for patients
with chronic hepatitis B are limited in both number and effectiveness; the
proven efficacy, good tolerability profile and apparently low potential for
resistance of adefovir dipivoxil make it a promising new option in the
management of this disease.Pharmacodynamic PropertiesAdefovir dipivoxil is
an oral diester prodrug of adefovir, a nucleotide analogue which, in its
active form (adefovir diphosphate), inhibits hepatitis B virus (HBV) DNA
polymerase. In vitro, the concentration of adefovir required to inhibit 50%
of HBV DNA synthesis ranged from 0.2-2.5 micro mol/L in a variety of HBV
DNA-producing human hepatoma cell lines. Additive antiviral effects were
observed when adefovir was combined with lamivudine, or with one of the
experimental drugs entecavir or telbivudine.No resistance-conferring HBV
mutations emerged in patients with chronic hepatitis B receiving adefovir
dipivoxil 10 or 30 mg/day for 48 weeks. After 96 weeks of treatment with
adefovir dipivoxil, a novel resistance-conferring substitution (asparagine
to threonine at position 236 of the HBV polymerase [rtN236T]) was identified
in HBV isolates from 2 of 124 patients (1.6%). In vitro, HBV carrying the
rtN236T substitution displayed reduced susceptibility to adefovir, but
remained sensitive to lamivudine. HBV mutants resistant to famciclovir or
lamivudine remained sensitive to adefovir dipivoxil and its active
metabolite.Pharmacokinetic PropertiesAdefovir dipivoxil is absorbed rapidly
following oral administration. The drug is cleaved to rug is cleaved to
adefovir which, in turn, is phosphorylated intracellularly to adefovir
diphosphate (the active moiety). Following a single dose of adefovir
dipivoxil, the bioavailability of adefovir was ≊59%. After 7 days of
treatment with adefovir dipivoxil 10 mg/day in 14 patients with chronic
hepatitis B, the mean peak plasma adefovir concentration, median time taken
to reach this concentration and the median area under the plasma
concentration-time curve were 18.3 ng/mL (≊67 nmol/L), 1 hour and 203 ng
· h/mL, respectively. Adefovir dipivoxil can be taken without regard
to meals.Adefovir is excreted renally as unchanged drug (steady-state renal
clearance [CL(R)] 154 mL/h/kg). The median steady-state terminal elimination
half-life was ≊7 hours in 14 patients with chronic hepatitis B. In
patients with moderate to severe renal dysfunction, the systemic exposure of
adefovir increased and the CL(R) decreased.In healthy volunteers, there were
no clinically relevant drug interactions when lamivudine, paracetamol
(acetaminophen), ibuprofen or cotrimoxazole (trimethoprim/sulfamethoxazole)
were coadministered with adefovir dipivoxil.Therapeutic Efficacy Once-daily
oral adefovir dipivoxil has been evaluated in five randomised, double-blind
trials in patients with chronic hepatitis B. Two were placebo-controlled
monotherapy trials in hepatitis B e antigen (HBeAg)-positive or -negative
patients, two investigated the use of adefovir dipivoxil as monotherapy and
in combination with lamivudine in patients infected with
lamivudine-resistant HBV and one compared adefovir dipivoxil plus lamivudine
with lamivudine plus placebo in treatment-naive patients. Several
noncomparative trials have studied the effects of adefovir dipivoxil in
specific patient populations.When compared with placebo, 48 weeks of
treatment with adefovir dipivoxil 10 mg/day resulted in significantly
greater histological, biochemical and virological improvements from baseline
in HBeAg-positive and -negative patients, and significantly greater
serological improvements in HBeAg-positive patients. In both HBeAg-positive
and -negative patients, the proportion of patients in the adefovir dipivoxil
groups showing histological improvement in the liver (primary endpoint) was
approximately twice the proportion showing improvement in the placebo groups
(53% vs 25% and 64% vs 33%, p < 0.001 for both).In patients chronically
infected with lamivudine-resistant HBV who had high serum HBV DNA and ALT
levels despite treatment with lamivudine, switching to adefovir dipivoxil or
adding adefovir dipivoxil to lamivudine produced a marked reduction in serum
HBV DNA and ALT levels, and was significantly more effective than continuing
with lamivudine monotherapy. In one trial, at week 16 the time-weighted
average change from baseline in HBV DNA levels (primary endpoint) was
significantly greater in the adefovir dipivoxil and adefovir dipivoxil plus
lamivudine groups than in the group receiving lamivudine alone
(≊−2.45 for both adefovir dipivoxil groups vs −0.07 log(10)
copies/mL, p < 0.001). In the other trial, a significantly higher
proportion of patients receiving adefovir dipivoxil plus lamivudine had a
serum HBV DNA response (≤10(5) copies/mL or reduction of ≥2 log(10)
copies/mL from baseline, primary endpoint) at weeks 48 and 52, compared with
patients receiving lamivudine plus placebo (85% vs 11%, p < 0.001). In
treatment-naive patients, 52 weeks of treatment with adefovir dipivoxil plus
lamivudine did not improve virological, biochemical or serological outcomes
compared with lamivudine plus placebo. Lamivudine-resistant HBV was observed
in significantly fewer patients in the adefovir dipivoxil plus lamivudine
group than in the lamivudine plus placebo group (20% vs 2%, p <
0.003).Adefovir dipivoxil also showed efficacy in a number of noncomparative
trials in a variety of patient types, including patients with decompensated
liver disease, patients co-infected with HIV, and pre- and post-liver
transplantation patients.TolerabilityAdefovir dipivoxil 10 mg/day is
generally well tolerated in patients with chronic HBV infection; there were
no marked increases in adverse events or laboratory abnormalities compared
with placebo in a pooled analysis of 48-week data from two double-blind
trials. Asthenia and diarrhoea occurred more frequently than with placebo in
one of the placebo-controlled studies, while headache and abdominal pain
occurred more frequently in the other study. Within 48 weeks, ≊2% of
patients from one study and no patients in the other study discontinued
treatment because of adverse events.US prescribing information indicates
that long-term administration of adefovir dipivoxil 10 mg/day may result in
nephrotoxicity, but that the risk in patients with adequate renal function
is low. In a pooled analysis of two placebo-controlled trials, no patients
at 48 weeks and 2 patients (<1%) at 96 weeks developed an increase in
serum creatinine levels of ≥0.5 mg/dL above baseline. One patient
discontinued treatment per protocol because of persistent serum creatinine
elevation, the other continued on therapy and the serum creatinine elevation
resolved.Increases in serum creatinine levels of ≥0.5 mg/dL above
baseline were observed in 13% of 324 patients awaiting or recovering from
liver transplantation who received adefovir dipivoxil 10 mg/day (48-week
data). The majority of these patients had renal insufficiency and/or risk
factors for renal dysfunction at baseline. The authors stated that, because
the patients had numerous other risk factors, it was difficult to determine
the extent to which adefovir dipivoxil contributed to the serum creatinine
elevations. Most of these patients continued treatment, some with dose
adjustments. One percent of patients discontinued treatment because of renal
adverse events.Dosage and AdministrationAdefovir dipivoxil is approved in
the US and the EU for chronic HBV infection. In the US, oral adefovir
dipivoxil 10 mg/day is indicated for the treatment of chronic hepatitis B in
patients with evidence of active viral replication and either histologically
active disease or persistent elevations in serum aminotransferases. For
patients with creatinine clearance <3 L/h (<50 mL/min) the dosage
interval should be adjusted. Renal function should be monitored in all
patients; patients receiving concomitant drugs that are excreted renally or
known to affect renal function should be closely monitored. Patients who
discontinue adefovir dipivoxil should be closely monitored for exacerbation
of hepatitis.

PMID: 14498759 [PubMed - as supplied by publisher]