TYZEKA™ is the trade name for telbivudine, a synthetic thymidine nucleoside analogue with activity against hepatitis B virus (HBV). The chemical name for telbivudine is 1-((2S,4R,5S)-4-hydroxy-5-hydroxymethyltetrahydrofuran-2-y1)-5-methyl-1H-pyrimidine-2,4-dione, or 1-(2-deoxy-β-L-ribofuranosyl)-5-methyluracil. Telbivudine is the unmodified β-L enantiomer of the naturally occurring nucleoside, thymidine. Its molecular formula is C₁₀H₁₄N₂O₅, which corresponds to a molecular weight of 242.23.

Telbivudine has the following structural formula:

Telbivudine is a white to slightly yellowish powder. Telbivudine is sparingly soluble in water (>20 mg/mL), and very slightly soluble in absolute ethanol (0.7 mg/mL) and n-octanol (0.1 mg/mL).

TYZEKA™ (telbivudine) film-coated tablets are available for oral administration in 600 mg strength. TYZEKA 600 mg film-coated tablets contain the following inactive ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate. The tablet coating contains titanium dioxide, polyethylene glycol, talc and hypromellose.

Microbiology

Mechanism of Action

Telbivudine is a synthetic thymidine nucleoside analogue with activity against HBV DNA polymerase. It is phosphorylated by cellular kinases to the active triphosphate form, which has an intracellular half-life of 14 hours. Telbivudine 5'-triphosphate inhibits HBV DNA polymerase (reverse transcriptase) by competing with the natural substrate, thymidine 5'-triphosphate. Incorporation of telbivudine 5'-triphosphate into viral DNA causes DNA chain termination, resulting in inhibition of HBV replication. Telbivudine is an inhibitor of both HBV first strand (EC₅₀ value = 1.3 ± 1.6 µM) and second strand synthesis (EC₅₀ value = 0.2 ±0.2 µM). Telbivudine 5'-triphosphate at concentrations up to 100 µM did not inhibit human cellular DNA polymerases α, β, or ν. No appreciable mitochondrial toxicity was observed in HepG2 cells treated with telbivudine at concentrations up to 10 µM.

Antiviral Activity

The antiviral activity of telbivudine was assessed in the HBV-expressing human hepatoma cell line 2.2.15, as well as in primary duck hepatocytes infected with duck hepatitis B virus. The concentration of telbivudine that effectively inhibited 50% of viral DNA synthesis (EC₅₀) in both systems was approximately 0.2 M. The anti-HBV activity of telbivudine was additive with adefovir in cell culture, and was not antagonized by the HIV NRTIs didanosine and stavudine. Telbivudine is not active against HIV-1 (EC₅₀ value >100 µM) and was not antagonistic to the anti-HIV activity of abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, or zidovudine.

Resistance

In an as-treated analysis of the Phase III global registration trial (007 GLOBE study), 59% (252/430) of treatment-naïve HBeAg-positive and 89% (202/227) of treatment-naïve HBeAg-negative patients receiving telbivudine 600 mg once daily achieved nondetectable serum HBV DNA levels (<300 copies/mL) by Week 52.

At Week 52, 145/430 (34%) and 19/227 (8%) of HBeAg-positive and HBeAg-negative telbivudine recipients, respectively, had evaluable HBV DNA ( ≥1,000 copies/mL). Genotypic analysis detected one or more amino acid substitutions associated with virologic failure (rtM204I, rtL80I/V, rtA181T, rtL180M, rtL229W/V) in 49 of 103 HBeAg-positive and 12 of 12 HBeAg-negative patients with amplifiable HBV DNA and ≥16 weeks of treatment. The rtM204I substitution was the most frequent mutation and was associated with virologic rebound (≥1 log₁₀ increase above nadir) in 34 of 46 patients with this mutation.

Cross-Resistance

Cross-resistance has been observed among HBV nucleoside analogues. In cell-based assays, lamivudine-resistant HBV strains containing either the rtM204I mutation or the rtL180M/rtM204V double mutation had 1,000-fold reduced susceptibility to telbivudine. Telbivudine retained wild-type phenotypic activity (1.2-fold reduction) against the lamivudine resistance-associated substitution rtM204V alone. The efficacy of telbivudine against HBV harboring the rtM204V mutation has not been established in clinical trials. HBV encoding the adefovir resistance-associated substitution rtA181V showed 3- to 5- fold reduced susceptibility to telbivudine in cell culture. HBV encoding the adefovir resistance-associated substitution rtN236T remained susceptible to telbivudine.

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