Disease relevance of Epavudine

• Median reductions in serum hepatitis B virus (HBV) DNA levels at week 52 (log(10) copies/mL) were as follows: lamivudine, 4.66; telbivudine 400 mg, 6.43; telbivudine 600 mg, 6.09; Comb400, 6.40; and Comb600, 6.05 [1].
• BACKGROUND & AIMS: A previous 4-week trial of telbivudine in patients with chronic hepatitis B indicated marked antiviral effects with good tolerability, leading to the present 1-year phase 2b trial [1].
• A dose-finding study of once-daily oral telbivudine in HBeAg-positive patients with chronic hepatitis B virus infection [2].
• Stereospecificity of human DNA polymerases alpha, beta, gamma, delta and epsilon, HIV-reverse transcriptase, HSV-1 DNA polymerase, calf thymus terminal transferase and Escherichia coli DNA polymerase I in recognizing D- and L-thymidine 5'-triphosphate as substrate [3].
• L-thymidine is phosphorylated by herpes simplex virus type 1 thymidine kinase and inhibits viral growth [4].

High impact information on Epavudine

• The results indicate that telbivudine was well tolerated at all dosing levels, with no dose-related or treatment-related clinical or laboratory adverse events. telbivudine plasma pharmacokinetics were dose-proportional within the studied dose range [2].
• Beta-L-thymidine 5'-triphosphate analogs as DNA polymerase substrates [5].
• The following anti-hepatitis B virus drugs are currently undergoing clinical testing: telbivudine, emtricitabine, tenofovir disoproxil fumarate, clevudine and thymosin-+/-1 [6].
• Pharmacokinetics of telbivudine in healthy subjects and absence of drug interaction with lamivudine or adefovir dipivoxil [7].
• Pharmacology of beta-L-thymidine and beta-L-2'-deoxycytidine in HepG2 cells and primary human hepatocytes: relevance to chemotherapeutic efficacy against hepatitis B virus [8].

Chemical compound and disease context of Epavudine

• CONCLUSIONS: Patients with chronic hepatitis B treated with telbivudine exhibited significantly greater virologic and biochemical responses compared with lamivudine [1].
• Kinetic studies with N2-phenylguanines and with L-thymidine indicate that herpes simplex virus type-1 thymidine kinase and thymidylate kinase share a common active site [9].
• Other newer antiviral agents such as emtricitabine, telbivudine and clevudine in the treatment of hepatitis B are still under phase II or III clinical trials [10].
• Idenix (formerly Novirio) and Novartis are developing two beta-L-deoxynucleosides, telbivudine and torcitabine, for the potential treatment of hepatitis B virus infection [11].
• In addition, several novel agents in clinical development, such as emtricitabine, clevudine, telbivudine, valtorcitabine, and tenofovir, have shown promising clinical profiles in patients with chronic hepatitis B [12].

Biological context of Epavudine

• Also the 5'-triphosphate of beta-L-thymidine (beta-L-TTP) was shown to be a strong inhibitor of these two viral enzymes (IC50 = 0.46/1.0 microM) [13].
• Values of Cmax, Tmax, and AUC were comparable when telbivudine was administered under fed and fasting conditions [14].
• Oral absorption of telbivudine as measured by maximum plasma concentration (Cmax), time to reach Cmax (Tmax), and area under the plasma concentration-time curve (AUC(0-t) and AUC(0-infinity)) was not altered by food intake immediately before oral dosing [14].
• We transformed synchronized mouse L-thymidine kinase deficient cells with a cloned thymidine kinase gene and carrier DNA at different times in the cell cycle [15].
• Additionally, in preclinical animal toxicology studies, telbivudine showed no adverse side effects or adverse effects on mitochondrial function [16].

Associations of Epavudine with other chemical compounds

• Two phase I studies were conducted to assess the plasma pharmacokinetics of telbivudine and potential drug-drug interactions between telbivudine (200 or 600 mg/day) and lamivudine (100 mg/day) or adefovir dipivoxil (10 mg/day) in healthy subjects [7].
• In vitro, unnatural L-enantiomers, except L-deoxycytidine, function as specific inhibitors for the viral enzyme in the order: L-thymidine >> L-deoxyguanosine > L-deoxyuridine > L-deoxyadenosine [17].
• This review focuses on the currently available medications for CHB: alpha-interferon, lamivudine, adefovir, as well as new drugs that have proven to be active against HBV in clinical trials and are closer to licensure; pegylated interferon tenofovir, entecavir, emtricitabine, telbivudine and clevudine [18].

Gene context of Epavudine

• In contrast to other nucleoside analogs, telbivudine has not been associated with inhibition of mammalian DNA polymerase with mitochondrial toxicity [19].

Analytical, diagnostic and therapeutic context of Epavudine

• Telbivudine was rapidly absorbed after oral administration, with the median times T(max) to the maximum plasma concentration (C(max)) ranging from 0.8 to 3.0 h postdosing across cohorts [20].
• The promising results of the early in vitro and animal telbivudine studies prompted the development and initiation of Phase I and II human clinical trials [16].
• In in vitro studies and animal models, telbivudine has demonstrated potent and specific antiviral activity against hepatitis B [16].
• After 52 weeks of telbivudine treatment there was an approximate 6-log reduction of hepatitis B virus DNA levels, hepatitis B virus DNA became undetectable by PCR assay in 61% of patients [21].

References