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Adefovir Dipivoxil (GS 0840)

Alias: GS 0840; GS0840; GS-0840; Hepsera; Preveon. Adefobir; GS-0393; GS-393; GS0393; GS393; GS 0393; GS 393; PMEA
Cat No.:V1815 Purity: ≥98%
Adefovir Dipivoxil (also known as GS 0840 and GS-0840; trade names Preveon and Hepsera), the dipivoxil formulation of adefovir, is a reverse transcriptase inhibitor, used in the treatment of chronic hepatitis B virus (HBV).
Adefovir Dipivoxil (GS 0840)
Adefovir Dipivoxil (GS 0840) Chemical Structure CAS No.: 142340-99-6
Product category: Reverse Transcriptase
This product is for research use only, not for human use. We do not sell to patients.
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Purity & Quality Control Documentation

Purity: ≥98%

Product Description

Adefovir Dipivoxil (also known as GS 0840 and GS-0840; trade names Preveon and Hepsera), the dipivoxil formulation of adefovir, is a reverse transcriptase inhibitor, used in the treatment of chronic hepatitis B virus (HBV). It is an antiviral acyclic nucleoside phosphonate (ANP) analog and a dipivoxil formulation of adefovir, a nucleoside reverse transcriptase inhibitor analog of adenosine with activity against hepatitis B virus (HBV), herpes virus, and human immunodeficiency virus (HIV). Adefovir Dipivoxil is an orally-administered acyclic nucleotide analog reverse transcriptase inhibitor (ntRTI) that works by blocking reverse transcriptase for the treatment of hepatitis B. Adefovir dipivoxil is not effective against HIV-1.

Biological Activity I Assay Protocols (From Reference)
ln Vitro

In vitro activity: 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.

ln Vivo
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.
Animal Protocol
1.0 mg/kg/day.
Mice
ADME/Pharmacokinetics
Absorption, Distribution and Excretion
The approximate oral bioavailability of adefovir from HEPSERA is 59%. When a single oral 10 mg dose is given to chronic hepatitis B patients, the peak plasma concentration (Cmax) of adefovir was 18.4 ± 6.26 ng/mL. This occurred between 0.58 - 4 hours post dose (Tmax). The adefovir area under the plasma concentration-time curve (AUC0–∞) was 220 ± 70.0 ng∙h/mL. Food does not affect the exposure of adeforvir.
Adefovir is renally excreted by a combination of glomerular filtration and active tubular secretion.
392 ± 75 mL/kg [Vd at steady state, intravenous administration of 1.0 mg/kg/day]
352 ± 9 mL/kg [Vd at steady state, intravenous administration of 3.0 mg/kg/day]
469 ± 99.0 mL/min [Patients with Unimpaired renal Function receiving a 10 mg single dose]
356 ± 85.6 mL/min [Patients with mild renal impairement receiving a 10 mg single dose]
237 ± 118 mL/min [Patients with moderate renal impairement receiving a 10 mg single dose]
91.7 ± 51.3 mL/min [Patients with severe renal impairement receiving a 10 mg single dose]
Metabolism / Metabolites
Following oral administration, adefovir dipivoxil is rapidly converted to adefovir. 45% of the dose is recovered as adefovir in the urine over 24 hours at steady state following 10 mg oral doses. Adefovir is not a substrate of the cytochrome P450 enzymes.
Biological Half-Life
Plasma adefovir concentrations declined in a biexponential manner with a terminal elimination half-life of 7.48 ± 1.65 hours.
Toxicity/Toxicokinetics
Protein Binding
≤4% over the adefovir concentration range of 0.1 to 25 μg/mL
References
Antiviral Res.2002 Jul;55(1):27-40.
Additional Infomation
Adefovir pivoxil is an organic phosphonate that is the dipivoxil ester of adefovir. A prodrug for adefovir, an HIV-1 reverse transcriptase inhibitor, adefovir pivoxil is used to treat chronic hepatitis B viral infection. It has a role as a prodrug, an antiviral drug, a DNA synthesis inhibitor, a HIV-1 reverse transcriptase inhibitor and a nephrotoxic agent. It is an organic phosphonate, a member of 6-aminopurines, an ether and a carbonate ester. It is functionally related to an adefovir.
Adefovir dipivoxil, previously called bis-POM PMEA, with trade names Preveon and Hepsera, is an orally-administered acyclic nucleotide analog reverse transcriptase inhibitor (ntRTI) used for treatment of hepatitis B. It is ineffective against HIV-1. Adefovir dipivoxil is the diester prodrug of adefovir.
Adefovir Dipivoxil is a dipivoxil formulation of adefovir, a nucleoside reverse transcriptase inhibitor analog of adenosine with activity against hepatitis B virus (HBV), herpes virus, and human immunodeficiency virus (HIV).
See also: Adefovir (has active moiety).
Drug Indication
Indicated for the treatment of chronic hepatitis B in adult patients with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease; this is based on histological, virological, biochemical, and serological responses in adult patients with HBeAg+ and HBeAg- chronic hepatitis B with compensated liver function, and in adult patients with clinical evidence of lamivudine-resistant hepatitis B virus with either compensated or decompensated liver function.
FDA Label
Hepsera is indicated for the treatment of chronic hepatitis B in adults with: compensated liver disease with evidence of active viral replication, persistently elevated serum-alanine-aminotransferase (ALT) levels and histological evidence of active liver inflammation and fibrosis. Initiation of Hepsera treatment should only be considered when the use of an alternative antiviral agent with a higher genetic barrier to resistance is not available or appropriate (see section 5. 1); decompensated liver disease in combination with a second agent without cross-resistance to Hepsera.
Mechanism of Action
Adefovir dipivoxil is a prodrug of adefovir. Adefovir is an acyclic nucleotide analog of adenosine monophosphate which is phosphorylated to the active metabolite adefovir diphosphate by cellular kinases. Adefovir diphosphate inhibits HBV DNA polymerase (reverse transcriptase) by competing with the natural substrate deoxyadenosine triphosphate and by causing DNA chain termination after its incorporation into viral DNA. The inhibition constant (Ki) for adefovir diphosphate for HBV DNA polymerase was 0.1 μM. Adefovir diphosphate is a weak inhibitor of human DNA polymerases α and γ with Ki values of 1.18 μM and 0.97μM, respectively.
Pharmacodynamics
Adefovir dipivoxil a diester prodrug of adefovir. Adefovir is an acyclic nucleotide analog with activity against human hepatitis B virus (HBV). The concentration of adefovir that inhibited 50% of viral DNA synthesis (IC50) in vitro ranged from 0.2 to 2.5 μM in HBV transfected human hepatoma cell lines. The combination of adefovir with lamivudine showed additive anti-HBV activity.
These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C20H32N5O8P
Molecular Weight
501.47
Exact Mass
501.198
CAS #
142340-99-6
Related CAS #
142340-99-6
PubChem CID
60871
Appearance
White to off-white solid powder
Density
1.4±0.1 g/cm3
Boiling Point
641.0±65.0 °C at 760 mmHg
Melting Point
98-102ºC
Flash Point
341.5±34.3 °C
Vapour Pressure
0.0±1.9 mmHg at 25°C
Index of Refraction
1.569
LogP
2.45
Hydrogen Bond Donor Count
1
Hydrogen Bond Acceptor Count
12
Rotatable Bond Count
15
Heavy Atom Count
34
Complexity
706
Defined Atom Stereocenter Count
0
InChi Key
WOZSCQDILHKSGG-UHFFFAOYSA-N
InChi Code
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)
Chemical Name
[2-(6-aminopurin-9-yl)ethoxymethyl-(2,2-dimethylpropanoyloxymethoxy)phosphoryl]oxymethyl 2,2-dimethylpropanoate
Synonyms
GS 0840; GS0840; GS-0840; Hepsera; Preveon. Adefobir; GS-0393; GS-393; GS0393; GS393; GS 0393; GS 393; PMEA
HS Tariff Code
2934.99.9001
Storage

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Shipping Condition
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
Solubility Data
Solubility (In Vitro)
DMSO: 100 mg/mL (199.4 mM)
Water:<1 mg/mL
Ethanol:100 mg/mL (199.4 mM)
Solubility (In Vivo)
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.

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.


 (Please use freshly prepared in vivo formulations for optimal results.)
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 1.9941 mL 9.9707 mL 19.9414 mL
5 mM 0.3988 mL 1.9941 mL 3.9883 mL
10 mM 0.1994 mL 0.9971 mL 1.9941 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

Calculator

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An example of molarity calculation using the molarity calculator is shown below:
What is the mass of compound required to make a 10 mM stock solution in 5 ml of DMSO given that the molecular weight of the compound is 350.26 g/mol?
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  • The answer of 17.513 mg appears in the Mass box. In a similar way, you may calculate the volume and concentration.

Dilution Calculator allows you to calculate how to dilute a stock solution of known concentrations. For example, you may Enter C1, C2 & V2 to calculate V1, as detailed below:

What volume of a given 10 mM stock solution is required to make 25 ml of a 25 μM solution?
Using the equation C1V1 = C2V2, where C1=10 mM, C2=25 μM, V2=25 ml and V1 is the unknown:
  • Enter 10 into the Concentration (Start) box and choose the correct unit (mM)
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  • The answer of 62.5 μL (0.1 ml) appears in the Volume (Start) box
g/mol

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Note: Chemical formula is case sensitive: C12H18N3O4  c12h18n3o4
Instructions to calculate molar mass (molecular weight) of a chemical compound:
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Definitions of molecular mass, molecular weight, molar mass and molar weight:
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In vivo Formulation Calculator (Clear solution)
Step 1: Enter information below (Recommended: An additional animal to make allowance for loss during the experiment)
Step 2: Enter in vivo formulation (This is only a calculator, not the exact formulation for a specific product. Please contact us first if there is no in vivo formulation in the solubility section.)
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Calculation results

Working concentration mg/mL;

Method for preparing DMSO stock solution mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.

Method for preparing in vivo formulation:Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O,mix and clarify.

(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
             (2) Be sure to add the solvent(s) in order.

Clinical Trial Information
Study Comparing the Safety of Switching From Lamivudine to Adefovir Dipivoxil Versus Overlapping Lamivudine and Adefovir Before Adefovir Dipivoxil Monotherapy in Patients With Chronic Hepatitis B
CTID: NCT00307242
Phase: Phase 4    Status: Completed
Date: 2021-11-12
A Study of Several Anti-HIV Drug Combinations in HIV-Infected Patients Who Have Used Indinavir
CTID: NCT00000892
Phase: N/A    Status: Completed
Date: 2021-11-04
The Effectiveness of Nelfinavir and Efavirenz, Used Alone or Together, Combined With Other Anti-HIV Drugs in Patients Who Have Taken Anti-HIV Drugs
CTID: NCT00001087
Phase: Phase 2    Status: Completed
Date: 2021-11-01
A Comparison of Adefovir and Tenofovir for the Treatment of Lamivudine-Resistant Hepatitis B Virus in People With HIV
CTID: NCT00033163
Phase: Phase 2    Status: Completed
Date: 2021-11-01
Treatment of Hepatitis in Patients Who Are Triple-Infected With HIV, Hepatitis B Virus (HBV), and Hepatitis C Virus (HCV)
CTID: NCT00051077
Phase: Phase 2    Status: Withdrawn
Date: 2021-11-01
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A Study on Amprenavir in Combination With Other Anti-HIV Drugs in HIV-Positive Patients
CTID: NCT00000912
Phase: Phase 2    Status: Completed
Date: 2021-10-29


Treatment Success and Failure in HIV-Infected Subjects Receiving Indinavir in Combination With Nucleoside Analogs: A Rollover Study for ACTG 320
CTID: NCT00000885
Phase: Phase 2    Status: Completed
Date: 2021-10-28
Lamivudine and Adefovir Dipivoxil Fixed Dose Combination
CTID: NCT01353742
Phase: Phase 1    Status: Completed
Date: 2017-08-04
HEPSERA Post Marketing Surveillance
CTID: NCT
A Multi-center, Randomized, Double-Blind, Active-Control, 96 Week, Phase III Trial of the Efficacy and Safety of Clevudine Compared with Adefovir at Weeks 48 and 96 in Nucleoside Treatment-Naïve Patients with HBeAg Negative Chronic Hepatitis due to Hepatitis B Virus
CTID: null
Phase: Phase 3    Status: Completed, Prematurely Ended
Date: 2007-06-28
A Multi-center, Randomized, Double-Blind, Active-Control, 96 Week, Phase III Trial of the Efficacy and Safety of Clevudine Compared with Adefovir at Weeks 48 and 96 in Nucleoside Treatment-Naïve Patients with HBeAg Positive Chronic Hepatitis due to Hepatitis B Virus
CTID: null
Phase: Phase 3    Status: Completed, Prematurely Ended
Date: 2007-06-28
Combined therapy with Adefovir and Interferon-Pegylated alfa 2a vs Adefovir alone, in patients affected by chronic hepatitis B, HbeAg negative (The PAC (Peg Adefovir Combination) Study).
CTID: null
Phase: Phase 3    Status: Prematurely Ended
Date: 2007-03-22
A Randomized, Double-Blind, Controlled Evaluation of Tenofovir DF versus Adefovir Dipivoxil for the Treatment of HBeAg Positive Chronic Hepatitis B.
CTID: null
Phase: Phase 3    Status: Completed
Date: 2005-07-21
A Randomized, Double-Blind, Controlled Evaluation of Tenofovir DF versus Adefovir Dipivoxil for the Treatment of Presumed Pre-core Mutant Chronic Hepatitis B
CTID: null
Phase: Phase 3    Status: Completed
Date: 2005-07-21
A Phase 3 Double-Blind Randomised, Placebo-Controlled Study of the safety and Efficacy of Adefovir Dipivoxil in Children and Adolescents (Age 2to <18) with Chronic Hepatitis B
CTID: null
Phase: Phase 3    Status: Completed
Date:

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