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Pharmacotherapeutic group: Antivirals for systemic use, 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 (TP) form, which has an intracellular half-life of 15 hours. By competing with the natural substrate deoxyguanosine TP, entecavir-TP functionally inhibits the 3 activities of the viral polymerase: priming of the HBV polymerase, reverse transcription of the negative strand DNA from the pregenomic messenger RNA, and synthesis of the positive strand HBV DNA. The entecavir-TP Ki for HBV DNA polymerase is 0.0012 μM. Entecavir-TP is a weak inhibitor of cellular DNA polymerases alpha, beta, and delta with Ki values of 18 to 40 μM. In addition, high exposures of entecavir had no relevant adverse effects on gamma polymerase or mitochondrial DNA synthesis in HepG2 cells (Ki > 160 μM).
Pharmacokinetics: Absorption: Entecavir is rapidly absorbed with peak plasma concentrations occurring between 0.5-1.5 hours. The absolute bioavailability has not been determined. Based on urinary excretion of unchanged drug, the bioavailability has been estimated to be at least 70%. There is a dose-proportionate increase in Cmax and AUC values following multiple doses ranging from 0.1-1 mg. Steady-state is achieved between 6-10 days after once daily dosing with ≈ 2 times accumulation. Cmax and Cmin at steady-state are 4.2 and 0.3 ng/ml, respectively, for a dose of 0.5 mg, and 8.2 and 0.5 ng/ml, respectively, for 1 mg.
Administration of 0.5 mg entecavir 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 (1-1.5 hour fed vs. 0.75 hour fasted), a decrease in Cmax of 44-46%, and a decrease in AUC of 18-20%. The lower Cmax and AUC when taken with food is not considered to be of clinical relevance in nucleoside-naïve 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. Following administration of 14C-entecavir, no oxidative or acetylated metabolites and minor amounts of the phase II metabolites, glucuronide and sulfate conjugates, were observed.
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.
Hepatic impairment: Pharmacokinetic parameters in patients with moderate or severe hepatic impairment were similar to those in patients with normal hepatic function.
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.
Post-liver transplant: Entecavir exposure in HBV-infected liver transplant recipients on a stable dose of ciclosporin A or tacrolimus was ≈ 2 times the exposure in healthy people with normal renal function. Altered renal function contributed to the increase in entecavir exposure in these patients.
Gender: AUC was 14% higher in women than in men, due to differences in renal function and weight. After adjusting for differences in creatinine clearance and body weight there was no difference in exposure between men and women.
Elderly: AUC was 29% higher in the elderly than in the young, mainly due to differences in renal function and weight. After adjusting for differences in creatinine clearance and body weight, the elderly had a 12.5% higher AUC than their counterpart. The population pharmacokinetic analysis covering patients in the age range 16-75 years did not identify age as significantly influencing entecavir pharmacokinetics.
Race: The population pharmacokinetic analysis did not identify race as significantly influencing entecavir pharmacokinetics. However, conclusions can only be drawn for the Caucasian and Asian groups as there were too little data in the other categories.
Paediatric population: The steady-state pharmacokinetics of entecavir were evaluated in nucleoside naïve and lamivudine-experienced HBeAg-positive paediatric population from 2 to < 18 years of age with compensated liver disease. Entecavir exposure among nucleoside naïve paediatric population receiving once daily doses of entecavir 0.015 mg/kg up to a maximum dose of 0.5 mg was similar to the exposure achieved in adults receiving once daily doses of 0.5 mg. Entecavir exposure among lamivudine-experienced paediatric population receiving once daily doses of entecavir 0.030 mg/kg up to a maximum dose of 1.0 mg was similar to the exposure achieved in adults receiving once daily doses of 1.0 mg.
