Adefovir Dipivoxil reduces Liver HBV DNA to<0.1 pg of viral DNA per mg of total DNA (pg/mg) in transgenic mice expressing hepatitis B virus. Adefovir Dipivoxil treatment also reduces serum HBV DNA to 3.5 log10 genomic equivalents (ge)/mL in transgenic mice expressing hepatitis B virus compared to 5.3 log10 ge/mL for the placebo control group. Adefovir Dipivoxil antiviral activity reaches near maximum viral reduction by day 10 in the liver and reaches an endpoint of liver virus inhibition at 1.0 mg/kg/day.

Absorption, Distribution and Excretion
The oral bioavailability of adefovir in HEPSERA formulations is approximately 59%. In patients with chronic hepatitis B, after a single oral dose of 10 mg adefovir, the peak plasma concentration (Cmax) was 18.4 ± 6.26 ng/mL, and the time to peak concentration (Tmax) ranged from 0.58 to 4 hours post-dose. The area under the plasma concentration-time curve (AUC0–∞) for adefovir was 220 ± 70.0 ng∙h/mL. Food does not affect adefovir exposure. Adefovir is primarily excreted via glomerular filtration and active tubular secretion through the kidneys.
392 ± 75 mL/kg [steady-state volume of distribution, 1.0 mg/kg/day intravenously]
352 ± 9 mL/kg [steady-state volume of distribution, 3.0 mg/kg/day intravenously]
469 ± 99.0 mL/min [single dose of 10 mg in patients with normal renal function]
356 ± 85.6 mL/min [single dose of 10 mg in patients with mild renal impairment]
237 ± 118 mL/min [single dose of 10 mg in patients with moderate renal impairment]
91.7 ± 51.3 mL/min [patients with severe renal impairment] [damage may occur after a single dose of 10 mg]

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Metabolism/Metabolites
After oral administration, adefovir dipivoxil is rapidly converted to adefovir. Following oral administration of 10 mg, under steady-state conditions, 45% of the dose is recovered in the urine and excreted as adefovir within 24 hours. Adefovir is not a substrate of cytochrome P450 enzymes.

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Biological Half-Life
Plasma adefovir concentration exhibits a biexponential decay, with a terminal elimination half-life of 7.48 ± 1.65 hours.

Protein Binding
Protein binding was less than 4% at adefovir concentrations ranging from 0.1 to 25 μg/mL.

Antiviral Res.2002 Jul;55(1):27-40.

Adefovir dipivoxil is an organophosphonate, specifically a dihydropyridine ester of adefovir. As a prodrug of adefovir, an HIV-1 reverse transcriptase inhibitor, adefovir dipivoxil is used to treat chronic hepatitis B virus infection. It has multiple functions, including as a prodrug, antiviral agent, DNA synthesis inhibitor, HIV-1 reverse transcriptase inhibitor, and nephrotoxic agent. It is an organophosphonate, belonging to the 6-aminopurine class of compounds, and is also an ether and carbonate. Its function is related to adefovir. Adefovir dipivoxil, formerly known as bis-POM PMEA, and marketed as Preveon and Hepsera, is an oral acyclic nucleotide analog reverse transcriptase inhibitor (ntRTI) used to treat hepatitis B. It is ineffective against HIV-1. Adefovir dipivoxil is a diester prodrug of adefovir.
Adefovir dipivoxil is a diester formulation of adefovir, a nucleoside reverse transcriptase inhibitor and an adenosine analogue active against hepatitis B virus (HBV), herpesvirus, and human immunodeficiency virus (HIV).
See also: Adefovir (active fraction).

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Indications
Indications for the treatment of adult patients with chronic hepatitis B who have evidence of viral replication activity and persistently elevated serum transaminases (ALT or AST) or histologically active disease; this study is based on histological, virological, biochemical, and serological responses in adult patients with compensated HBeAg-positive and HBeAg-negative chronic hepatitis B, as well as adult patients with compensated or decompensated hepatic function and clinical evidence of lamivudine-resistant hepatitis B virus.
FDA Label
Hepsera is indicated for the treatment of chronic hepatitis B in adults who meet the following criteria: compensated liver function, evidence of active viral replication, persistently elevated serum alanine aminotransferase (ALT) levels, and histological evidence of liver inflammation and fibrosis. Hepsera should only be considered for initiation of treatment when alternative antiviral agents with higher genetic barriers to resistance are unavailable or unsuitable (see Section 5.1). In cases of decompensated liver disease, in combination with another drug that does not exhibit cross-resistance with Hepsera, it is also indicated.

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Mechanism of Action
Adefovir dipivoxil is a prodrug of adefovir. Adefovir is a noncyclic nucleotide analog of adenosine monophosphate, phosphorylated by cellular kinases to its active metabolite, adefovir diphosphate. Adefovir diphosphate inhibits HBV DNA polymerase (reverse transcriptase) by competing with its natural substrate, deoxyadenosine triphosphate, and by causing DNA chain termination upon incorporation into viral DNA. Adefovir diphosphate has an inhibitory constant (Ki) of 0.1 μM against HBV DNA polymerase. Adefovir diphosphate is a weak inhibitor of human DNA polymerase α and γ, with Ki values of 1.18 μM and 0.97 μM, respectively.

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Pharmacodynamics
Adefovir dipivoxil is a diester prodrug of adefovir. Adefovir is an acyclic nucleotide analog with activity against human hepatitis B virus (HBV). In vitro, the concentration of adefovir that inhibits 50% of viral DNA synthesis (IC50) in HBV-transfected human hepatocellular carcinoma cell lines ranges from 0.2 to 2.5 μM. Combination therapy of adefovir with lamivudine shows synergistic anti-HBV activity.

C20H32N5O8P

501.47

501.198

142340-99-6

60871

White to off-white solid powder

1.4±0.1 g/cm3

641.0±65.0 °C at 760 mmHg

98-102ºC

341.5±34.3 °C

0.0±1.9 mmHg at 25°C

1.569

2.45

1

12

15

34

706

0

WOZSCQDILHKSGG-UHFFFAOYSA-N

InChI=1S/C20H32N5O8P/c1-19(2,3)17(26)30-11-32-34(28,33-12-31-18(27)20(4,5)6)13-29-8-7-25-10-24-14-15(21)22-9-23-16(14)25/h9-10H,7-8,11-13H2,1-6H3,(H2,21,22,23)

[2-(6-aminopurin-9-yl)ethoxymethyl-(2,2-dimethylpropanoyloxymethoxy)phosphoryl]oxymethyl 2,2-dimethylpropanoate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.99 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (4.99 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (4.99 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)