209216-23-9

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• Antiviral drugs

  Entecavir hydrate is a new kind of cyclopentyl acyl guanosine anti-hepatitis b virus drugs with its pharmacological effects similar as entecavir. It is clinically applied to the treatment of adult chronic hepatitis b in which there is active viral replication, increased serum transaminase ALT or active lesions showed from liver histology.
  This product is a kind of analogues of guanine nucleoside which has inhibitory on the polymerase of hepatitis b virus (HBV). It can become active triphosphate salts through phosphorylation. The triphosphate salt has a half-life of 15 hours inside a cell. Through completion with the natural substrates of HBV polymerase, guanine nucleoside triphosphate, entecavir triphosphate can suppress all the three types of activities of the virus polymerase (reverse transcriptase):
  (1) The initiation of HBV polymerase.
  (2) The formation of the negative chain of reverse transcription of the pre-genome.
  (3) The synthesis of HBVDNA positive chain.
  The inhibition kinetic constant (Ki) of entecavir triphosphate on the HBV DNA polymerase is 0.0012 μM. Entecavir triphosphate has a relative low inhibitory effect on the alpha, beta, and delta DNA polymerase gamma and mitochondria DNA polymerase inside cells with the Ki value being 18 to 160 μM.
  The above information is edited by the chemicalbook of Dai Xiongfeng. ;

• Antiviral activity

  In the transfected human HepG2 cells with wild type of hepatitis b virus, the 50% inhibition concentration (EC50) of entecavir in inhibiting the virus DNA synthesis is about 0.004 μM. The median value of the EC50 of entecavir on the inhibition of lamivudine resistant strains (rtL180M rtM204V) is 0.026 μM (range: 0.01 to 0.059 μM). However, entecavir has no clinically relevant effect on the growth of the in type 1 human immunodeficiency virus (HIV) on the cell culture (EC50 > 10 μM). Daily or weekly administration of this product can reduce the DNA level of hepatitis b virus of North American marmot and duck. Long-term studies on 5 North America marmot have shown that oral administration of 0.5 mg/kg entecavir per week (equivalent to the dose of 1.0 mg to the human body) can maintain the viral DNA in undetectable level for three marmot (HBV DNA levels < 200 copies/mL, PCR method) for as long as three years. In any animals which have subject to treatment of this drug for up to three years, there have been no cases of the HBV polymerase’s resistances on the entecavir. ;

• Drug resistance

  In vitro studies: it was found in the cell assay, lamivudine resistant strains has a 8-30 fold decreased dominant sensitivity to entecavir. If the hepatitis b virus polymerase has already contains the amino acid substitutions engaged in lamivudine resistance (rtL180M and/or rtM204V/I), further plus rtT184, rtS202 or rtM250 loci displacement variation, or on the basis of simultaneously occurrence of the above two kinds of variation, whether or not rtI169 displacement variation occurs, the virus has a much more reduced dominant susceptibility to entecavir (> 70 times).
  Cross resistance: it has been already found of the cross-resistance phenomenon of the nucleoside analogue drugs of anti-hepatitis b virus. It was found in the cell test that entecavir has an 8 to 30 fold reduced inhibitory effects on the lamivudine resistant (rtL180M and/or rtM204V/I) strains than wild strains. Entecavir is also sensitive to the recombinant virus with adefovir resistant variation (HBV DNA polymerase rtN236T or rtA181V variation). In vitro experiments have shown, virus species isolated from patients to whom lamivudine and entecavir are ineffective, are still sensitive to adefovir, but still kept the lamivudine resistance. ;

• Pharmacokinetic

  Absorption, after oral administration of this drug among healthy people, the product is rapidly absorbed with the plasma concentration reaching peak (Cmax) at about 0.5 to 1.5 hours. Administrate this drug once pay day with the drug concentration reaching steady-state after 6 to 10 days with the cumulative amount of about two times.
  The effect of food on the oral absorption: the dietary standard: administrating 0.5 mg of this product simultaneously with either high fat diet or low-fat meal can cause a slight delay of the drug absorption (from the original 0.75 hours to 1.0~1.5 hours), Cmax is reduced by 44%~46%, and the area under the curve (AUC) during medication is reduced by 18%~20%. Therefore, this product should be taken on an empty stomach (before a meal or at least 2 hours after meals).
  Distribution: pharmacokinetic data have showed that the apparent volume of distribution is over the whole body fluid which demonstrates that this product is widely distributed in the organization. In vitro experiments have shown that the combination rate of this product with human plasma protein is about 13%.
  Metabolism and clearance: during the assay of administration of 14C labeled entecavir to human and rats, it had been observed of any oxidation or acetylation metabolites of this drug, but instead observed of a small amount of phase II metabolites such as glucuronic acid conjugates or sulphuric acid conjugates. Entecavir is not the substrate, inhibitor or inducer of the cytochrome P450 (CYP450) enzyme system. After it reaching peak plasma concentration, blood drug concentration decreases in double index manner with the half-life of reaching terminal clearance being about 128~149 hours. Drug cumulative index is 2 times the amount of the daily administrated dosage, demonstrating that the half-life of the effective accumulation being about 24 hours. This drug is mainly subject to kidney clearance in its prototype form with the clearance rate being the 62%~73% of its dosage and the kidney clearance being 360~471 ml/min, and being independent on the drug dose, which suggests that entecavir is excreted simultaneously through the glomerular filtration and the reticular tubular. ;

• Clinical evaluation

  1. Entecavir has a very strong antiviral capacity with long-term application only yielding a low drug resistance rate. It may have a direct inhibitory effect on the cccDNA in liver cells which can effectively treat chronic hepatitis b with its curative effect being superior to lamivudine.
  2. Endeavor’s treatment of patients (first subject to this drug) for the first one year has the incidence of drug resistance being 0. However, for the YMDD mutant resistant patients, the resistant incidence increases to 5.8%. 3. It was found in the cell test that entecavir has an 8 to 30 fold reduced inhibitory effects on the lamivudine resistant (rtL180M and/or rtM204V/I) strains than wild strains. Therefore, for the treatment of patients with lamivudine resistance, the dosage should be increased to 1.0 mg. Entecavir is also sensitive to the recombinant virus with adefovir resistant variation (HBV DNA polymerase rtN236T or rtA181V variation). In vitro experiments have shown, entecavir resistant virus are still sensitive to adefovir, but still kept the lamivudine resistance. ;

• Adverse reactions and the matters which needs attention

  In the clinical trials in China, the most common adverse reactions are: ALT elevations, fatigue, dizziness, nausea, abdominal pain, abdominal discomfort, upper abdominal pain, liver area discomfort, muscle pain, insomnia, and rubella. These adverse reactions are mostly mild to moderate. In the comparison experiments together with lamivudine, this product has a similar incidence of adverse events as lamivudine.
  In patients with renal insufficiency, the orally clearance rate of orally administrated entecavir decreases with the decreased rate of creatinine clearance. Patients of creatinine clearance < 50 ml/min (including patients undergoing hemodialysis or CAPD treatment) should subject to dosage adjustment.
  Research on the effects of entecavir on pregnant women is not sufficient. Only after adequate weigh of both the potential risks as well as benefit to the fetus can the product be applied. There is currently no data suggesting this product can affect the mother-to-child transmission of HBV. Therefore, appropriate intervention measures should be taken to prevent neonatal HBV infection. Entecavir can be secreted from milk of rats. But whether there is also the case in human milk is still not clear for which it is recommend that the mother who takes this drug have breastfeeding. ;

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