Adefovir Dipivoxil (GS 0840) acts as a chain terminator nucleotide analog and is effective against some retroviruses, herpesviruses, and hepadnaviruses including HBV. Resistance of HBV to lamivudine does not confer resistance to Adefovir Dipivoxil (GS 0840), making this drug potentially clinically important. Natural killer cell activity and interferon production were enhanced in human patients by administration of Adefovir Dipivoxil (GS 0840). Adefovir Dipivoxil (GS 0840) is in phase 3 of clinical trials for treatment of HBV in human patients. [1]

Adefovir Dipivoxil works by blocking reverse transcriptase, an enzyme that is crucial for the hepatitis B virus (HBV) to reproduce in the body. Adefovir Dipivoxil works by blocking reverse transcriptase, an enzyme that is crucial for the hepatitis B virus (HBV) to reproduce in the body. Adefovir Dipivoxil is used for treatment of hepatitis B and herpes simplex virus infection.

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Hepatitis B virus (HBV) polymerase (reverse transcriptase) [1]

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.
Adefovir Dipivoxil (GS 0840) reduced liver HBV DNA to <0.1 pg of viral DNA per μg of total DNA (pg/μg) following oral therapy at 100 mg/kg/day twice daily for 10 days as compared to a mean of 3.0 pg/μg for placebo control group. Oral Adefovir Dipivoxil (GS 0840) also reduced serum HBV DNA to 3.5 log10 genomic equivalents (ge)/ml compared to 5.3 log10 ge/ml for placebo control group. With once daily treatments, antiviral activity reached near maximum viral reduction by day 10 in the liver and reached an endpoint of liver virus inhibition at 1.0 mg/kg/day. The minimum effective dose was less than 0.1 mg/kg/day using inhibition of serum virus. Liver HBV RNA was not reduced by oral Adefovir Dipivoxil (GS 0840) treatments. [1]
In a time-course study, oral Adefovir Dipivoxil (GS 0840) at 100 mg/kg/day progressively reduced HBV virus load in the liver on days 2 through 21. By day 7 the virus load was strongly reduced; by day 10 virus titers were near limits of detection. Serum HBV DNA was statistically lower than placebo at days 4, 7, 10 and 21. [1]
In a dose-range study, once daily oral Adefovir Dipivoxil (GS 0840) at doses down to 1.0 mg/kg/day significantly lowered liver HBV DNA (mean 3.3 pg/μg cell DNA) compared to placebo (10.5 pg/μg). Doses of 0.32 and 0.10 mg/kg/day did not significantly reduce liver HBV DNA. Serum HBV DNA was reduced over 2 log10 (P<0.001) at all dosages used (100, 32, 10, 3.2, 1.0, 0.32, 0.10 mg/kg/day). [1]

1.0 mg/kg/day. Mice

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Transgenic mice expressing hepatitis B virus (HBV) (derived from founder 1.3.32, both males and females, weight 18-24 g) were used. Adefovir Dipivoxil (GS 0840) was dispersed in 0.4% carboxymethylcellulose (CMC) as a particulate solution or in citric acid (0.05 M, pH 4.0) to enhance solubility. In one experiment, a dose of 50 mg/kg of Adefovir Dipivoxil (GS 0840) was given twice daily by oral gavage to achieve a total dose of 100 mg/kg/day for 10 days. In other experiments, half-log dilutions of Adefovir Dipivoxil (GS 0840) (100, 32, 10, 3.2, 1.0, 0.32, 0.10 mg/kg/day) were given orally once daily for 10-21 days. For the time-course study, mice were treated once daily with Adefovir Dipivoxil (GS 0840) at 100 mg/kg/day or saline until sacrifice on days 2, 4, 7, 10, and 21. For the dose-range study, groups of five male and five female mice were treated once daily for 14 days with half-log dilutions of Adefovir Dipivoxil (GS 0840) in 0.4% CMC (100 to 3.2 mg/kg/day) or in citric acid (3.2 to 0.1 mg/kg/day). In a separate experiment to verify antiviral activity, mice were treated bid with oral Adefovir Dipivoxil (GS 0840) at 100 mg/kg/day for 10 days, with saline-treated and untreated groups as controls. On the last day of treatment, mice were sacrificed 2-4 h after the morning treatment to obtain liver and serum samples. [1]

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.

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

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No toxicity, as observed with no altered morbidity or mortality, was apparent at the highest dosage of Adefovir Dipivoxil (GS 0840) used (100 mg/kg/day). [1]

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.

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Adefovir Dipivoxil (GS 0840) is an ester prodrug of adefovir (9-(2-phosphonylmethoxyethyl)adenine, PMEA). An ester moiety was added to the parent drug, PMEA, which provided better bioavailability and uptake of the drug in human patients. Adefovir Dipivoxil (GS 0840) inhibits replication of HBV through chain termination of the RNA to viral DNA. A previous transgenic mouse model expressing low levels of HBV was inadequate to quantify the extent of virus reduction by Adefovir Dipivoxil (GS 0840); the present study quantified the reduction. Phase I/II clinical trials showed that HBV-infected patients receiving oral Adefovir Dipivoxil (GS 0840) at 125 mg once daily for 28 days reduced HBV DNA levels by a mean of 1.8 log10 pg/ml. One patient had seroconversion to hepatitis B e antigen after 12 weeks. Adefovir Dipivoxil (GS 0840) also provides anti-HBV activity against lamivudine-resistant strains of HBV, which may make the compound important in combination therapies. [1]

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.)