Adefovir Dipivoxil (Page 5 of 9)

Hepatic Impairment

The pharmacokinetics of adefovir following a 10 mg single dose of adefovir dipivoxil have been studied in non-chronic hepatitis B patients with hepatic impairment. There were no substantial alterations in adefovir pharmacokinetics in patients with moderate and severe hepatic impairment compared to unimpaired patients. No change in adefovir dipivoxil dosing is required in patients with hepatic impairment.

12.4 Microbiology

Mechanism of Action

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 microM. Adefovir diphosphate is a weak inhibitor of human DNA polymerases α and γ with Ki values of 1.18 microM and 0.97 microM, respectively.

Antiviral Activity

The concentration of adefovir that inhibited 50% of viral DNA synthesis (EC50 ) in HBV transfected human hepatoma cell lines ranged from 0.2 to 2.5 microM. The combination of adefovir with lamivudine in cell culture was not antagonistic.

Resistance

Clinical isolates with genotypic changes conferring reduced susceptibility in cell culture to nucleoside analog reverse transcriptase inhibitors for the treatment of HBV infection have been observed. Long-term resistance analyses performed by genotyping samples from all adefovir dipivoxil-treated patients with detectable serum HBV DNA demonstrated that amino acid substitutions rtN236T and rtA181T/V have been observed in association with adefovir resistance. In cell culture, the rtN236T substitution demonstrated 4- to 14-fold, the rtA181V substitution 2.5- to 4.2-fold, and the rtA181T substitution 1.3- to 1.9-fold reduced susceptibility to adefovir.

In HBeAg-positive nucleoside-naïve patient isolates (Study GS-98-437, N=171), no adefovir resistance-associated substitutions were observed at Week 48. Sixty-five patients continued on long term treatment after a median duration on adefovir dipivoxil of 235 weeks (range 110 to 279 weeks). Isolates from 16 of 38 (42%) patients developed adefovir resistance-associated substitutions in the setting of virologic failure (confirmed increase of at least 1 log10 HBV DNA copies/mL above nadir or never suppressed below 103 copies/mL). The substitutions included rtN236T (N=2), rtA181V (N=4), rtA181T (N=3), rtA181T+rtN236T (N=5), and rtA181V+rtN236T (N=2). In HBeAg-negative nucleoside-naïve patients (Study GS-98-438), isolates from 30 patients were identified with adefovir resistance-associated substitutions with a cumulative probability of 0%, 3%, 11%, 19%, and 30% at 48, 96, 144, 192, and 240 weeks, respectively. Of those 30 patients, 22 had a confirmed increase of at least 1 log10 HBV DNA copies/mL above nadir or never achieved HBV DNA levels below 103 copies/mL; an additional 8 patients had adefovir resistance-associated substitutions without virologic failure. In addition, the long term (4 to 5 years) development of resistance to adefovir dipivoxil was significantly lower in patients who had serum HBV DNA below the limit of quantification (less than 1,000 copies/mL) at Week 48 as compared to patients who had serum HBV DNA above 1,000 copies/mL at Week 48.

In an open-label study of pre- and post-liver transplantation patients (Study GS-98-435), isolates from 129 patients with clinical evidence of lamivudine-resistant hepatitis B virus at baseline were evaluated for adefovir resistance-associated substitutions. The incidence of adefovir resistance-associated (rtN236T or rtA181T/V) substitutions was 0% at 48 weeks. Isolates from four patients developed the rtN236T substitution after 72 weeks of adefovir dipivoxil therapy. Development of the rtN236T substitution was associated with serum HBV DNA rebound. All 4 patients who developed the rtN236T substitution in their HBV had discontinued lamivudine therapy before the development of genotypic resistance and all 4 lost the lamivudine resistance-associated substitutions present at baseline. In a study of 35 HIV/HBV co-infected patients with lamivudine-resistant HBV (Study 460i) who added adefovir dipivoxil to lamivudine, no adefovir resistance-associated substitutions were observed in HBV isolates from 15/35 patients tested up to 144 weeks of therapy.

Clinical resistance in pediatric patients

In a Phase 3 pediatric Study GS-US-103-518, HBV isolates from 49 of 56 pediatric subjects (aged 12 to 17 years) had serum HBV DNA greater than 169 copies/mL and were evaluated for adefovir resistance-associated substitutions. rtN236T and/or rtA181V adefovir resistance-associated substitutions were not observed at Week 48. However, the rtA181T substitution was present in baseline and Week 48 isolates from 2 pediatric patients.

Cross-resistance

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.

HBV isolates expressing rtA181T, rtA181V, or rtN236T single substitutions that are associated with resistance to adefovir had less than 2-fold changes in EC50 values to tenofovir and tenofovir alafenamide. However, the HBV isolate expressing the rtA181V plus rtN236T double substitutions exhibited reduced susceptibility to tenofovir (2.8-fold) and tenofovir alafenamide (3.7-fold). The clinical relevance of these substitutions is not known.

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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term oral carcinogenicity studies of adefovir dipivoxil in mice and rats were carried out at exposures up to approximately 10 times (mice) and 4 times (rats) those observed in humans at the therapeutic dose for HBV infection. In both mouse and rat studies, adefovir dipivoxil was negative for carcinogenic findings. Adefovir dipivoxil was mutagenic in the in vitro mouse lymphoma cell assay (with or without metabolic activation). Adefovir induced chromosomal aberrations in the in vitro human peripheral blood lymphocyte assay without metabolic activation. Adefovir dipivoxil was not clastogenic in the in vivo mouse micronucleus assay and adefovir was not mutagenic in the Ames bacterial reverse mutation assay using S. typhimurium and E. coli strains in the presence or absence of metabolic activation. In reproductive toxicology studies, no evidence of impaired fertility was seen in male or female rats at systemic exposure approximately 19 times that achieved in humans at the therapeutic dose.

13.2 Animal Toxicology and/or Pharmacology

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 to 10 times higher than those in humans at the recommended therapeutic dose of 10 mg/day.

14 CLINICAL STUDIES

14.1 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 adefovir dipivoxil. 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 log10 copies/mL and a median ALT level of 2.3 times the upper limit of normal.

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