Recombinant HBV variants containing lamivudine-resistance-associated substitutions (rtL180M, rtM204I, rtM204V, rtL180M + rtM204V, rtV173L + rtL180M + rtM204V) were susceptible to adefovir in cell culture. Adefovir dipivoxil has also demonstrated anti-HBV activity (median reduction in serum HBV DNA of 4.1 log₁₀ copies/mL) in patients with HBV containing lamivudine-resistance-associated substitutions (study 435). Adefovir also demonstrated in cell culture activity against HBV variants with entecavir resistance-associated substitutions (rtT184G, rtS202I, rtM250V). HBV variants with DNA polymerase substitutions rtT128N and rtR153Q or rtW153Q associated with resistance to hepatitis B virus immunoglobulin were susceptible to adefovir in cell culture.

HBV variants expressing the adefovir resistance-associated substitution rtN236T showed no change in susceptibility to entecavir in cell culture, and a 2- to 3-fold decrease in lamivudine susceptibility. HBV mutants with the adefovir resistance-associated substitution rtA181V showed a range of decreased susceptibilities to lamivudine of 1- to 14-fold and a 12-fold decrease in susceptibility to entecavir. In patients whose HBV expressed the rtA181V substitution (n=2) or the rtN236T substitution (n=3), a reduction in serum HBV DNA of 2.4 to 3.1 and 2.0 to 5.1 log₁₀ copies/mL, respectively, was observed when treatment with lamivudine was added to treatment with adefovir dipivoxil.

Animal Toxicology and/or Pharmacology

Toxicology Studies

Animal reproduction studies were conducted in rats and rabbits with orally administered adefovir dipivoxil and intravenously administered adefovir.

In rats and rabbits, no embryotoxicity or teratogenicity was shown from oral administration of adefovir dipivoxil at maternal doses producing systemic exposures approximately 23 times (rats) and 40 times (rabbits) that achieved in humans at the therapeutic dose of 10 mg/day.

When pregnant rats were administered intravenous adefovir at maternally toxic doses associated with systemic exposure 38 times that in humans, embryotoxicity and an increased incidence of fetal malformations (anasarca, depressed eye bulge, umbilical hernia, and kinked tail) were observed. No adverse effects on development were seen with intravenous adefovir administered to pregnant rats at a systemic exposure 12 times that in humans.

Animal Toxicology Studies

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.

Clinical Studies

Studies 437 and 438 (Pivotal Studies)

HBeAg-Positive Chronic Hepatitis B

Study 437 was a randomized, double-blind, placebo-controlled, three-arm study in patients with HBeAg-positive chronic hepatitis B that allowed for a comparison between placebo and HEPSERA. The median age of patients was 33 years. Seventy-four percent were male, 59% were Asian, 36% were Caucasian, and 24% had prior interferon-α treatment. At baseline, patients had a median total Knodell Histology Activity Index (HAI) score of 10, a median serum HBV DNA level as measured by the Roche Amplicor Monitor polymerase chain reaction (PCR) assay (LLOQ = 1000 ^{copies/mL) of 8.36 log}10 copies/mL and a median ALT level of 2.3 times the upper limit of normal.

HBeAg-Negative (Anti-HBe Positive/HBV DNA Positive) Chronic Hepatitis B

Study 438 was a randomized, double-blind, placebo-controlled study in patients who were HBeAg-negative at screening, and anti-HBe positive. The median age of patients was 46 years. Eighty-three percent were male, 66% were Caucasian, 30% were Asian and 41% had prior interferon-α treatment. At baseline, the median total Knodell HAI score was 10, the median serum HBV DNA level as measured by the Roche Amplicor Monitor PCR assay (LLOQ = 1000 copies/mL) was 7.08 log₁₀ copies/mL, and the median ALT was 2.3 times the upper limit of normal.

The primary efficacy endpoint in both studies was histological improvement at week 48; results of which are shown in Table 4.

Table 4. Histological Response at Week 48*

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