BARACLUDER is the tradename for entecavir, a guanosine nucleoside analogue with selective activity against hepatitis B virus (HBV). The chemical name for entecavir is 2-amino-l,9-dihydro-9-[(1S 3R 4S)-4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]- 6H-purin-6-one, monohydrate. Its molecular formula is C₁₂H₁₅N₅O₃•H₂O, which corresponds to a molecular weight of 295.3. Entecavir has the following structural formula:

Entecavir is a white to off-white powder. It is slightly soluble in water (2.4 mg/mL), and the pH of the saturated solution in water is 7.9 at 25° ± 0.5° C.

BARACLUDE film-coated tablets are available for oral administration in strengths of 0.5 mg and 1 mg of entecavir. BARACLUDE 0.5-mg and 1-mg film-coated tablets contain the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, crospovidone, povidone, and magnesium stearate. The tablet coating contains titanium dioxide, hypromellose, polyethylene glycol 400, polysorbate 80 (0.5-mg tablet only), and iron oxide red (1-mg tablet only). BARACLUDE Oral Solution is available for oral administration as a ready-to-use solution containing 0.05 mg of entecavir per milliliter. BARACLUDE Oral Solution contains the following inactive ingredients: maltitol, sodium citrate, citric acid, methylparaben, propylparaben, and orange flavor.

Microbiology

Mechanism of Action

Entecavir, a guanosine nucleoside analogue with activity against HBV polymerase, is efficiently phosphorylated to the active triphosphate form, which has an intracellular half-life of 15 hours. By competing with the natural substrate deoxyguanosine triphosphate, entecavir triphosphate functionally inhibits all three activities of the HBV polymerase (reverse transcriptase, rt): (1) base priming, (2) reverse transcription of the negative strand from the pregenomic messenger RNA, and (3) synthesis of the positive strand of HBV DNA. Entecavir triphosphate is a weak inhibitor of cellular DNA polymerases a, B, and 8 and mitochondrial DNA polymerase γ with K_i values ranging from 18 to > 160µM.

Antiviral Activity

Entecavir inhibited HBV DNA synthesis (50% reduction, EC₅₀) at a concentration of 0.004µM in human HepG2 cells transfected with wild-type HBV. The median EC₅₀ value for entecavir against lamivudine-resistant HBV (rtL180M, rtM204V) was 0.026 µM (range 0.010-0.059 µM). The coadministration of HIV nucleoside reverse transcriptase inhibitors (NRTIs) with BARACLUDE is unlikely to reduce the antiviral efficacy of BARACLUDE against HBV or of any of these agents against HIV. In HBV combination assays in cell culture, abacavir, didanosine, lamivudine, stavudine, tenofovir, or zidovudine were not antagonistic to the anti-HBV activity of entecavir over a wide range of concentrations. In HIV antiviral assays, entecavir was not antagonistic to the cell culture anti-HIV activity of these six NRTIs at > 4 times the Cmax of entecavir.

Antiviral Activity against HIV

A comprehensive analysis of the inhibitory activity of entecavir against a panel of laboratory and clinical human immunodeficiency virus type 1 (HIV-1) isolates using a variety of cells and assay conditions yielded EC₅₀ values ranging from 0.026 to > 10 µM; the lower EC₅₀ values were observed when decreased levels of virus were used in the assay. In cell culture, entecavir selected for an Ml 841 substitution in HIV reverse transcriptase at micromolar concentrations, confirming inhibitory pressure at high entecavir concentrations. HIV variants containing the Ml84V substitution showed loss of susceptibility to entecavir.

Resistance

In Cell Culture

In cell-based assays, 8- to 30-fold reductions in entecavir phenotypic susceptibility were observed for lamivudine-resistant strains. Further reductions (> 70-fold) in entecavir phenotypic susceptibility required the presence of amino acid substitutions rtM204I/V and/or rtL180M along with additional substitutions at residues rtT184, rtS202, or rtM250, or a combination of these substitutions with or without an rtI169 substitution in the HBV polymerase.

Clinical Studies

Nucleoside-naive subjects: Genotypic evaluations were performed on evaluable samples (> 300 copies/mL serum HBV DNA) from 562 subjects who were treated with BARACLUDE for up to 96 weeks in nucleoside-naive studies (AI463022, AI463027, and rollover study AI463901). By Week 96, evidence of emerging amino acid substitution rtS202G with rfM204V and rtL180M substitutions was detected in the HBV of 2 subjects (2/562 = < 1%), and 1 of them experienced virologic rebound (≥ 1 log₁₀ increase above nadir). Emerging amino acid substitutions at rtM204I/V ± rtL180M, rtL80I, or rtV173L, which conferred decreased phenotypic susceptibility to entecavir, were detected in the HBV of 3 subjects (3/562 = < 1%) who experienced virologic rebound.

Lamivudine-refractory subjects: Genotypic evaluations were performed on evaluable samples from 190 subjects treated with BARACLUDE for up to 96 weeks in studies of lamivudine-refractory HBV (AI463026, AI463014, AI463015, and rollover study AI463901). By Week 96, resistance amino acid substitutions at rtS202, rtT184, rtI169 ± rtM250 in the presence of amino acid substitutions rtM204I/V ± rfL180M, rfL80V, or rtV173L/M emerged in the HBV from 22 subjects (22/190 = 12%), 16 of whom experienced virologic rebound (≥ 1 log₁₀ increase above nadir) and 4 of whom were never suppressed < 300 copies/mL. The HBV from 4 of these subjects had entecavir resistance substitutions at baseline and acquired further changes on entecavir treatment. In addition to the 22 subjects, 3 subjects experienced virologic rebound with the emergence of rtM204I/V ± rtL180M, rtL80V, or rtV173L/M. For isolates from subjects who experienced virologic rebound with the emergence of resistance substitutions (n=19), the median fold-change in entecavir EC₅₀ values from reference was 19-fold at baseline and 106-fold at the time of virologic rebound.

Cross-resistance

Cross-resistance has been observed among HBV nucleoside analogues. In cell-based assays, entecavir had 8- to 30-fold less inhibition of HBV DNA synthesis for HBV containing lamivudine and telbivudine resistance substitutions rtM204I/V ± rtL180M than for wild-type HBV. Substitutions rtM204I/V ± rtL180M, rtL80I/V, or rtV173L, which are associated with lamivudine and telbivudine resistance, also confer decreased phenotypic susceptibility to entecavir. Recombinant HBV genomes encoding adefovir resistance-associated substitutions at either rtN236T or rtA181V had 0.3- and 1.1-fold shifts in susceptibility to entecavir in cell culture, respectively. The efficacy of entecavir against HBV harboring adefovir resistance-associated substitutions has not been established in clinical trials. HBV isolates from lamivudine-refractory subjects failing entecavir therapy were susceptible in cell culture to adefovir but remained resistant to lamivudine.

Bookmark this page: