Benavir Mechanism of Action

Pharmacotherapeutic group: Antivirals for systemic use, nucleoside and nucleotide reverse transcriptase inhibitors. ATC code: J05AF10.
Pharmacology: Pharmacodynamics: Mechanism of Action: Entecavir is a guanosine nucleoside analogue with potent and selective activity against Hepatitis B Virus (HBV) polymerase. It is phosphorylated to the active triphosphate (TP) form, which has an intracellular half-life of 15 hours. Intracellular TP levels are directly related to extracellular entecavir concentrations, with no significant accumulation beyond initial plateau levels. By competing with the natural substrate deoxyguanosine-TP, entecavir-TP inhibits all 3 functional activities of the viral polymerase: (1) priming of the HBV polymerase, (2) reverse transcription of the negative strand from the pregenomic messenger RNA, and (3) synthesis of the positive strand HBV DNA. The entecavir-TP Ki for HBV DNA polymerase is 1.2 nM. Entecavir-TP is a weak inhibitor of cellular DNA polymerases α, β, and δ with Ki values of 18 to 40 μM. In addition, high exposures of entecavir-TP and entecavir had no relevant adverse effects on γ polymerase (Ki >160 μM) or mitochondrial DNA synthesis in HepG2 cells.
Antiviral activity: Entecavir inhibited HBV DNA synthesis (50% reduction, EC₅₀) at a concentration of 0.004 μM in human HepG2 cells transfected with wild-type HBV. The median EC₅₀ value for entecavir against lamivudine-resistant HBV (rtM204V, rtL180M) was 0.026 μM (range 0.010-0.059 μM). Recombinant viruses encoding adefovir-resistant substitutions at either rtN236T or rtA181V remained fully susceptible to entecavir.
EC₅₀ of entecavir against laboratory and clinical HIV-1 isolates in a variety of cells and assay conditions ranged from 0.026 to >10 μM; the lower EC₅₀ values were observed in decreased levels of virus in the assay. In cell culture, entecavir selected for an M184I substitution at micromolar concentrations, confirming inhibitory pressure at high entecavir concentrations. HIV variants containing the M184V substitution showed loss of susceptibility to entecavir.
Pharmacokinetics: Absorption: Entecavir is rapidly absorbed with peak plasma concentrations occurring between 0.5 and 1.5 hours. The bioavailability has been estimated to be at least 70% based on urinary excretion of unchanged drug. There is a dose-proportionate increase in (C_max) and (AUC) values following multiple doses ranging from 0.1 to 1 mg. Steady-state was achieved after 6-10 days of once-daily dosing with approximately 2-fold accumulation. C_max and trough plasma concentration (C_min) at steady-state were 4.2 and 0.3 ng/mL, respectively, for a 0.5-mg dose, and 8.2 and 0.5 ng/mL, respectively, for a 1-mg dose.
Oral administration of entecavir 0.5 mg with a standard high-fat meal (945 kcal, 54.6 g fat) or a light meal (379 kcal, 8.2 g fat) resulted in a minimal delay in absorption (1.0-1.5 hours fed vs. 0.75 hour fasted), a decrease in C_max of 44-46%, and a decrease in AUC of 18-20%. The lower C_max and AUC when taken with food is not considered to be of clinical relevance in nucleoside-naive patients but could affect efficacy in lamivudine-refractory patients.
Distribution: The estimated volume of distribution for entecavir is in excess of total body water. Protein binding to human serum protein in vitro is ≈ 13%.
Biotransformation: Entecavir is not a substrate, inhibitor or inducer of the CYP450 enzyme system. Based on the available data, following administration of ₁₄C-entecavir, no oxidative or acetylated metabolites and minor amounts of the phase II metabolites, glucuronide and sulfate conjugates readings were documented.
Elimination: Entecavir is predominantly eliminated by the kidney with urinary recovery of unchanged drug at steady-state of about 75% of the dose. Renal clearance is independent of dose and ranges between 360-471 mL/min suggesting that entecavir undergoes both glomerular filtration and net tubular secretion. After reaching peak levels, entecavir plasma concentrations decreased in a bi-exponential manner with a terminal elimination half-life of ≈ 128-149 hours. The observed drug accumulation index is ≈ 2 times with once daily dosing, suggesting an effective accumulation half-life of about 24 hours.
Special Populations: Patients with renal impairment: Entecavir clearance decreases with decreasing creatinine clearance. A 4-hour period of haemodialysis removed ≈ 13% of the dose, and 0.3% was removed by CAPD.
Patients with hepatic impairment: Pharmacokinetic parameters of entecavir in patients with hepatic impairment were similar to those in patients with normal hepatic function.
Gender: There was no differences in exposure (AUC) between male and female gender.
Race: The population pharmacokinetic analysis did not identify race as significantly influencing entecavir pharmacokinetics.
Liver transplant recipients: HBV-infected liver transplant recipients exhibit increased entecavir exposure due to altered renal function.
Elderly: Pharmacokinetic profile of entecavir does not differ by age.