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Pharmacotherapeutic group: Nucleoside and nucleotide reverse transcriptase inhibitors. ATC Code: J05AF10.
Pharmacology: Pharmacodynamics: 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): Base priming; Reverse transcription of the negative strand from the pregenomic messenger RNA; Synthesis of the positive strand of HBV DNA.
Entecavir triphosphate has an inhibition constant (Ki) for HBV DNA polymerase of 0.0012 μM. It is a weak inhibitor of cellular DNA polymerases (alpha), (beta), and (delta) and mitochondrial DNA polymerase (gamma) with Ki values ranging from 18 to >160 μM.
Pharmacokinetics: Absorption: Following oral administration in healthy subjects, entecavir peak plasma concentrations occurred between 0.5 and 1.5 hours.
Effects of food on oral absorption: Oral administration of 0.5 mg of entecavir with a standard high-fat meal or a light meal resulted in a delay in absorption (1.0-1.5 hours fed vs. 0.75 hours fasted), a decrease in Cmax of 44-46%, and a decrease in AUC of 18-20%.
Distribution: Based on the pharmacokinetic profile of entecavir after oral dosing, the estimated apparent volume of distribution is in excess of total body water, suggesting that entecavir is extensively distributed into tissues.
Binding of entecavir to human serum proteins in vitro was approximately 13%.
Metabolism and elimination: Following administration of 14C-entecavir in humans, no oxidative or acetylated metabolites were observed. Minor amounts of phase II metabolites (glucuronide and sulfate conjugates) were observed. Entecavir is not a substrate, inhibitor, or inducer of the cytochrome P450 (CYP450) enzyme system.
After reaching peak concentration, entecavir plasma concentrations decreased in a bi-exponential manner with a terminal elimination half-life of approximately 128-149 hours. The observed drug accumulation index is approximately 2-fold with once-daily dosing, suggesting an effective accumulation half-life of approximately 24 hours.
Entecavir is predominantly eliminated by the kidney with urinary recovery of unchanged drug at steady state ranging from 62% to 73% of the administered dose. Renal clearance is independent of dose and ranges from 360 to 471 ml/min suggesting that entecavir undergoes both glomerular filtration and net tubular secretion.
