Adefovir Dipivoxil

Adefovir dipivoxil, previously called bis-POM PMEA, with trade names Preveon and Hepsera, is an orally-administered acyclic nucleotide analog reverse transcriptase inhibitor (ntRTI) used for treatment of hepatitis B. It is ineffective against HIV-1. Adefovir dipivoxil is the diester prodrug of adefovir.

Adefovir dipivoxil is a nucleotide analog used to treat chronic hepatitis B.

Indicated for the treatment of chronic hepatitis B in adult patients with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease; this is based on histological, virological, biochemical, and serological responses in adult patients with HBeAg+ and HBeAg- chronic hepatitis B with compensated liver function, and in adult patients with clinical evidence of lamivudine-resistant hepatitis B virus with either compensated or decompensated liver function.

• Hepatitis B Chronic Infection

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.

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.

The approximate oral bioavailability of adefovir from HEPSERA is 59%. When a single oral 10 mg dose is given to chronic hepatitis B patients, the peak plasma concentration (Cmax) of adefovir was 18.4 ± 6.26 ng/mL. This occurred between 0.58 - 4 hours post dose (Tmax). The adefovir area under the plasma concentration-time curve (AUC0–∞) was 220 ± 70.0 ng∙h/mL. Food does not affect the exposure of adeforvir.

• 392 ± 75 mL/kg [Vd at steady state, intravenous administration of 1.0 mg/kg/day]
• 352 ± 9 mL/kg [Vd at steady state, intravenous administration of 3.0 mg/kg/day]

≤4% over the adefovir concentration range of 0.1 to 25 μg/mL

Adefovir is renally excreted by a combination of glomerular filtration and active tubular secretion.

Plasma adefovir concentrations declined in a biexponential manner with a terminal elimination half-life of 7.48 ± 1.65 hours.

• 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]

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.

• Take with or without food. The absorption is unaffected by food.