| Indication |
For the treatment of chronic hepatitis B in adults with evidence
of active viral replication and either evidence of persistent elevations
in serum aminotransferases (ALT or AST) or histologically active
disease. |
| Pharmacodynamics |
Adefovir dipivoxil a diester prodrug of adefovir. Adefovir is an
acyclic nucleotide analog with activity against human hepatitis B virus
(HBV). The concentration of adefovir that inhibited 50% of viral DNA
synthesis (IC50) in vitro ranged from 0.2 to 2.5 μM in HBV transfected
human hepatoma cell lines. The combination of adefovir with lamivudine
showed additive anti-HBV activity. |
| Mechanism of action |
Adefovir dipivoxil is a prodrug of adefovir. Adefovir is an
acyclic nucleotide analog of adenosine monophosphate which is
phosphorylated to the active metabolite adefovir diphosphate by cellular
kinases. Adefovir diphosphate inhibits HBV DNA polymerase (reverse
transcriptase) by competing with the natural substrate deoxyadenosine
triphosphate and by causing DNA chain termination after its
incorporation into viral DNA. The inhibition constant (Ki) for adefovir
diphosphate for HBV DNA polymerase was 0.1 μM. Adefovir diphosphate is a
weak inhibitor of human DNA polymerases α and γ with Ki values of 1.18
μM and 0.97μM, respectively. |
| Absorption |
Approximate oral bioavailability is 59%. |
| Volume of distribution |
- 392 ± 75 mL/kg [intravenous administration of 1.0 mg/kg/day]
- 352 ± 9 mL/kg [intravenous administration of 3.0 mg/kg/day]
|
| Protein binding |
≤4% over the adefovir concentration range of 0.1 to 25 μg/mL |
| Metabolism |
Following oral administration, adefovir dipivoxil is rapidly
converted to adefovir. Forty-five percent of the dose is recovered as
adefovir in the urine over 24 hours at steady state following 10 mg oral
doses. Adefovir is not a substrate of the cytochrome P450 enzymes. |
| Route of elimination |
Adefovir is renally excreted by a combination of glomerular filtration and active tubular secretion. |
| Half life |
Terminal elimination half-life of 7.48 ± 1.65 hours |
| Clearance |
- 469 +/- 99.0 mL/min [Patients with Unimpaired renal Function receiving a 10 mg single dose]
- 356 +/- 85.6 mL/min [Patients with mild renal impairement receiving a 10 mg single dose]
- 237 +/- 118 mL/min [Patients with moderate renal impairement receiving a 10 mg single dose]
- 91.7+/- 51.3 mL/min [Patients with severe renal impairement receiving a 10 mg single dose]
|
| Toxicity |
Renal tubular nephropathy characterized by histological
alterations and/or increases in BUN and serum creatinine was the primary
dose-limiting toxicity associated with administration of adefovir
dipivoxil in animals. Nephrotoxicity was observed in animals at systemic
exposures approximately 3–10 times higher than those in humans at the
recommended therapeutic dose of 10 mg/day. |
