Hepatitis B Virus
Physiological Effect: The entecavir EC50 of a laboratory hepatitis b virus isolate in cell culture is roughly 5.3 nm (nanometres). This suggests that entecavir is very responsive, even at low doses. In two relevant animal models, daily or weekly entecavir treatment significantly reduced viral levels. Long-term studies demonstrated that oral weekly dosing of 1 mg/kg maintained viral DNA levels at undetectable levels for up to three years. No entecavir resistance changes were detected in the hepatitis B virus polymerase in any of the treated animals for up to three years of treatment.
Following oral administration in healthy subjects, entecavir peak plasma concentrations occurred between 0.5 and 1.5 hours. Following multiple daily doses ranging from 0.1 to 1.0 mg, Cmax and area under the concentration time curve at steady state increased in proportion to dose. In healthy subjects, the bioavailability of the tablet was 100% relative to the oral solution. Moreover, following administration of entecavir in humans and rats, no oxidative or acetylated metabolites were observed. Entecavir is not a substrate, inhibitor, or inducer of the cytochrome P450 enzyme in the liver.
After reaching peak concentration, entacavir plasma concentrations decreased in a bi-exponential manner with a terminal elimination half-life of approximately 128 to 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. The chemical compound 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 the drug undergoes both glomerular filtration and net tubular secretion. Although rare, side-effects include headache, fatigue, dizziness, and nausea.