Pharmacodynamic (Mechanism of Action):
- Entecavir, a deoxyguanosine nucleoside analogue with activity against HBV reverse
transcriptase (rt), 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 reverse transcriptase: (1) base priming, (2) reverse transcription of
the negative strand from the pregenomic messenger RNA, and (3) synthesis of the positive
strand of HBV DNA.
Entecavir peak plasma concentrations occurred between 0.5 and 1.5 hours. Following
multiple daily doses ranging from 0.1 to 1 mg, (Cmax) and area under the concentration-time
curve (AUC) at steady state increased in proportion to dose. Steady state was achieved after
6 to 10 days of once-daily administration with approximately 2-fold accumulation. For a
0.5mg oral dose, Cmax at steady state was 4.2 ng/mL and trough plasma concentration (Ctrough)
was 0.3 ng/mL. For a 1 mg oral dose, Cmax was 8.2 ng/mL and Ctrough was 0.5 ng/mL. The
bioavailability of the tablet was 100% relative to the oral solution. The oral solution and
tablet may be used interchangeably. Effects of food on oral absorption: Oral administration
of 0.5 mg of 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 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%.
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%.
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.
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.