Drug Groups

approved; investigational

Description

Adefovir dipivoxil, previously called bis-POM PMEA, with trade names Preveon and Hepsera, is an orally-administered nucleotide analog reverse transcriptase inhibitor (ntRTI) used for treatment of hepatitis B. It is a failed treatment for HIV. [Wikipedia]

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.

Pharmacology

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.

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.

Affected Organisms

Biotransformation

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.

Absorption

Approximate oral bioavailability is 59%.

Half Life

Terminal elimination half-life of 7.48 ± 1.65 hours

Protein Binding

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

Elimination

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

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]

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]

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