Indications
Adefovir Dipivoxil is indicated for the treatment of chronic hepatitis B in adult patients who demonstrate active viral replication. This indication extends to cases exhibiting either ongoing elevated serum aminotransferase levels (ALT or AST) or histologically active disease. The efficacy of Adefovir Dipivoxil is supported by a range of responses-histological, virological, biochemical, and serological-in adult patients with both HBeAg-positive and HBeAg-negative chronic hepatitis B, provided there is compensated liver function. Additionally, the treatment is appropriate for adult patients showing clinical evidence of lamivudine-resistant hepatitis B virus, regardless of whether they have compensated or decompensated liver function.
Pharmacodynamics
Adefovir Dipivoxil functions as a diester prodrug of adefovir, which is an acyclic nucleotide analog with antiviral activity against the hepatitis B virus (HBV). In vitro studies involving HBV-transfected human hepatoma cell lines revealed that adefovir has an inhibitory concentration (IC50) ranging from 0.2 to 2.5 μM, effectively suppressing 50% of viral DNA synthesis. Moreover, when used in combination with lamivudine, adefovir shows additive effects in combating HBV.
Absorption
The oral bioavailability of adefovir from HEPSERA is approximately 59%. In patients with chronic hepatitis B receiving a single oral dose of 10 mg, the peak plasma concentration (Cmax) of adefovir is 18.4 ± 6.26 ng/mL, typically occurring between 0.58 and 4 hours post-dose (Tmax). The area under the plasma concentration-time curve (AUC0-∞) is recorded at 220 ± 70.0 ng·h/mL. Notably, food intake does not influence the exposure levels of adefovir.
Metabolism
Upon oral administration, adefovir dipivoxil is swiftly converted into adefovir. At steady state, following 10 mg oral doses, approximately 45% of the dose is excreted in the urine as adefovir over a 24-hour period. Importantly, adefovir is not processed by the cytochrome P450 enzyme system, indicating that it does not undergo significant hepatic metabolism via these enzymes.
Mechanism of Action
Adefovir Dipivoxil functions as a prodrug, converting into the active compound adefovir upon metabolic activation. Adefovir is an acyclic nucleotide analog of adenosine monophosphate, which undergoes phosphorylation by cellular kinases to form the active metabolite, adefovir diphosphate. This metabolite plays a crucial role in inhibiting the HBV DNA polymerase, also known as reverse transcriptase, by competing with deoxyadenosine triphosphate, the natural substrate. Furthermore, adefovir diphosphate contributes to the termination of the viral DNA chain following its integration into the viral genome. The compound demonstrates a significant inhibition constant (Ki) of 0.1 μM for HBV DNA polymerase. While adefovir diphosphate shows weak inhibitory effects on human DNA polymerases α and γ, the Ki values for these interactions are measured at 1.18 μM and 0.97 μM, respectively.
