Adefovir Dipivoxil

Clinical use is limited to HBV infections, including lamivudine-resistant HBV strains. Oral ade-fovir dipivoxil shows dose-dependent inhibition of hepadnavirus replication. In vitro combinations of adefovir and lamivudine or other anti-HBV nucleosides show enhanced antihepadnavirus activity.

mechanisms of action and resistance Adefovir dipivoxil enters cells and is deesterified to adefovir. Cellular enzymes convert adefovir to the diphosphate, which competitively inhibits viral DNA polymerases and reverse transcriptases and also serves as a chain terminator of viral DNA synthesis. Its selectivity relates to a higher affinity for HBV DNA polymerase compared with cellular polymerases. The intracellular t1/2 of the diphosphate is prolonged and once-daily

dosing is feasible. Adefovir resistance has been detected in ~4% of chronically infected HBV patients during 3 years of treatment, reflecting unique point mutations in the HBV polymerase. The consequences of emerging resistance remain to be determined.

ABSORPTION, DISTRIBUTION, AND ELIMINATION

The parent compound has low oral bioavailability (<12%), whereas the dipivoxil prodrug is absorbed rapidly and hydrolyzed by esterases in the intestine and blood to adefovir. Adefovir bioavailability is ~30-60%. Food does not affect bioavailability. Adefovir has low protein binding (<5%) and has a volume of distribution similar to body water (~0.4 L/kg).

Adefovir is renally excreted. After oral administration of adefovir dipivoxil, ~30-45% of the dose is recovered unchanged in urine within 24 hours; the elimination t/2 is 5—7.5 hours. Dose reductions are indicated for ClCr values <50 mL/min. Adefovir is removed by hemodialysis.

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