Singapore Drugs Database

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.

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.

Pharmacokinetics

Absorption

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.

Distribution

* 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]

Metabolism

Following oral administration, adefovir dipivoxil is rapidly converted to adefovir. 45% 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.

Elimination

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.

Active Ingredient/Synonyms

Adefovir di(pivaloyloxymethyl) ester | Adefovir Pivoxil | bis-POM PMEA | Adefovir Dipivoxil |