Drugs

, Volume 63, Issue 20, pp 2215–2234 | Cite as

Adefovir Dipivoxil

A Review of its Use in Chronic Hepatitis B
Adis Drug Evaluation

Summary

Abstract

Adefovir dipivoxil (Hepsera®) 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 Properties

Adefovir 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 μmol/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 Properties

Adefovir dipivoxil is absorbed rapidly following oral administration. The drug 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 [CLr] 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 CLr 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 log10 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 (≤105 copies/mL or reduction of ≥2 logio 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.

Tolerability

Adefovir 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 Administration

Adefovir 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.

Keywords

Lamivudine Adefovir HBeAg Seroconversion Adefovir Dipivoxil Receive Adefovir Dipivoxil 

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© Adis Data Information BV 2003

Authors and Affiliations

  1. 1.Adis International LimitedMairangi BayNew Zealand

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