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Adefovir Dipivoxil
- 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.
- pharmacologypharmacology:
- mechanism: 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.
- 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.
- absorprion: Approximate oral bioavailability is 59%.
- halflife: Terminal elimination half-life of 7.48 ± 1.65 hours
- roouteelimination: Adefovir is renally excreted by a combination of glomerular filtration and active tubular secretion.
- volumedistribution: * 392 ± 75 mL/kg [intravenous administration of 1.0 mg/kg/day] * 352 ± 9 mL/kg [intravenous administration of 3.0 mg/kg/day]
- 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]