Adefovir dipivoxil

Identification

Summary

Adefovir dipivoxil is a nucleotide analog used to treat chronic hepatitis B.

Brand Names
Hepsera
Generic Name
Adefovir dipivoxil
DrugBank Accession Number
DB00718
Background

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.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 501.4705
Monoisotopic: 501.198849537
Chemical Formula
C20H32N5O8P
Synonyms
  • Adefovir di(pivaloyloxymethyl) ester
  • Adefovir dipivoxil
  • Adefovir pivoxil
  • bis-POM PMEA
External IDs
  • GS 0840
  • GS-0840

Pharmacology

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.

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Management ofChronic hepatitis b••••••••••••
Contraindications & Blackbox Warnings
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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.

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.

TargetActionsOrganism
ADNA polymerase/reverse transcriptase
other
HBV-D
Absorption

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.

Volume of distribution
  • 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]
Protein binding

≤4% over the adefovir concentration range of 0.1 to 25 μg/mL

Metabolism

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.

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Route of elimination

Adefovir is renally excreted by a combination of glomerular filtration and active tubular secretion.

Half-life

Plasma adefovir concentrations declined in a biexponential manner with a terminal elimination half-life of 7.48 ± 1.65 hours.

Clearance
  • 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]
Adverse Effects
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Toxicity

Renal tubular nephropathy characterized by histological alterations and/or increases in BUN and serum creatinine was the primary dose-limiting toxicity associated with administration of adefovir dipivoxil in animals. Nephrotoxicity was observed in animals at systemic exposures approximately 3–10 times higher than those in humans at the recommended therapeutic dose of 10 mg/day.

Pathways
PathwayCategory
Adefovir Dipivoxil Metabolism PathwayDrug metabolism
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbacavirAdefovir dipivoxil may decrease the excretion rate of Abacavir which could result in a higher serum level.
AceclofenacThe risk or severity of nephrotoxicity can be increased when Adefovir dipivoxil is combined with Aceclofenac.
AcemetacinThe risk or severity of nephrotoxicity can be increased when Adefovir dipivoxil is combined with Acemetacin.
AcetaminophenAdefovir dipivoxil may decrease the excretion rate of Acetaminophen which could result in a higher serum level.
AcetazolamideThe excretion of Adefovir dipivoxil can be decreased when combined with Acetazolamide.
Food Interactions
  • Take with or without food. The absorption is unaffected by food.

Products

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Active Moieties
NameKindUNIICASInChI Key
Adefovirprodrug6GQP90I798106941-25-7SUPKOOSCJHTBAH-UHFFFAOYSA-N
International/Other Brands
A Di Xian (The United Laboratories Ltd) / A Gan Ding (Fujian Guangsheng Tang) / Adesera (Cipla) / Adfovir (Sun Pharmaceutical Industries Ltd.) / Ailuwei (Changzheng-Xinkai) / Antiva (Square) / Biovir (Ivax) / Dai Ding (Tianjin Institute of Pharmaceutical Research) / Dinghe (Lukang) / Infovir (Incepta) / Jiule (Fovir Pharm) / Lifuzhi (Jiangsu TianShiLi BeiTe Pharmaceutical Co., Ltd.) / Ming Zheng (Chia Tai Tianqing) / Nafasera (Vidipha) / Preveon (Gilead Sciences, Inc.) / Pymefovir (PMP) / Xinfunuo (SL Pharm) / Yilaifen (Qilu)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
HepseraTablet10 mgOralGilead Sciences2006-04-182022-12-21Canada flag
HepseraTablet10 mgOralGilead Sciences Ireland Uc2016-09-082023-03-06EU flag
HepseraTablet10 mg/1OralGilead Sciences, Inc.2002-09-202023-10-31US flag
HepseraTablet10 mgOralGilead Sciences Ireland Uc2016-09-082023-03-06EU flag
HepseraTablet10 mg/1OralExcella Gmb H2002-09-20Not applicableUS flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Aa-adefovirTablet10 mgOralAa Pharma Inc2014-08-07Not applicableCanada flag
Adefovir dipivoxilTablet10 mg/1OralApotex Corp.2018-09-25Not applicableUS flag
Adefovir DipivoxilTablet10 mg/1OralSigmapharm Laboratories, LLC2013-09-03Not applicableUS flag

Categories

ATC Codes
J05AF08 — Adefovir dipivoxil
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as 6-aminopurines. These are purines that carry an amino group at position 6. Purine is a bicyclic aromatic compound made up of a pyrimidine ring fused to an imidazole ring.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Imidazopyrimidines
Sub Class
Purines and purine derivatives
Direct Parent
6-aminopurines
Alternative Parents
Aminopyrimidines and derivatives / Dialkyl alkylphosphonates / Phosphonic acid esters / N-substituted imidazoles / Imidolactams / Dicarboxylic acids and derivatives / Heteroaromatic compounds / Amino acids and derivatives / Carboxylic acid esters / Azacyclic compounds
show 6 more
Substituents
6-aminopurine / Amine / Amino acid or derivatives / Aminopyrimidine / Aromatic heteropolycyclic compound / Azacycle / Azole / Carbonyl group / Carboxylic acid derivative / Carboxylic acid ester
show 19 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
  • Hepatitis B virus

Chemical Identifiers

UNII
U6Q8Z01514
CAS number
142340-99-6
InChI Key
WOZSCQDILHKSGG-UHFFFAOYSA-N
InChI
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)
IUPAC Name
[({[2-(6-amino-9H-purin-9-yl)ethoxy]methyl}({[(2,2-dimethylpropanoyl)oxy]methoxy})phosphoryl)oxy]methyl 2,2-dimethylpropanoate
SMILES
CC(C)(C)C(=O)OCOP(=O)(COCCN1C=NC2=C(N)N=CN=C12)OCOC(=O)C(C)(C)C

References

Synthesis Reference
US4808716
General References
Not Available
Human Metabolome Database
HMDB0014856
KEGG Drug
D01655
KEGG Compound
C11277
PubChem Compound
60871
PubChem Substance
46507520
ChemSpider
54855
BindingDB
50248359
RxNav
141400
ChEBI
31175
ChEMBL
CHEMBL922
ZINC
ZINC000003930376
Therapeutic Targets Database
DNC001135
PharmGKB
PA10005
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Adefovir
FDA label
Download (293 KB)
MSDS
Download (57 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedBasic ScienceHealthy Volunteers (HV)1
4CompletedTreatmentChronic Hepatitis B Infection12
4CompletedTreatmentChronic Hepatitis B Infection / Cirrhosis of the Liver / Fibrosis1
4CompletedTreatmentHBeAg(-) Chronic Hepatitis B With Compensated Liver Function1
4CompletedTreatmentViral Hepatitis B1

Pharmacoeconomics

Manufacturers
  • Gilead sciences inc
Packagers
  • A-S Medication Solutions LLC
  • Excella GmbH
  • Gilead Sciences Inc.
  • Patheon Inc.
Dosage Forms
FormRouteStrength
TabletOral
TabletOral10 mg/1
TabletOral10 mg
Prices
Unit descriptionCostUnit
Hepsera 10 mg tablet30.32USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US5663159No1997-09-022014-09-02US flag
CA2298057No2008-11-182018-07-23Canada flag
CA2051239No2003-03-252011-09-12Canada flag
US6451340No2002-09-172018-07-23US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubility19 mg/mL at pH 2.0 and 0.4 mg/mL at pH 7.2.FDA label
logP1.91FDA label
Predicted Properties
PropertyValueSource
Water Solubility0.633 mg/mLALOGPS
logP1.49ALOGPS
logP3.06Chemaxon
logS-2.9ALOGPS
pKa (Strongest Acidic)18.55Chemaxon
pKa (Strongest Basic)3.75Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count8Chemaxon
Hydrogen Donor Count1Chemaxon
Polar Surface Area166.98 Å2Chemaxon
Rotatable Bond Count15Chemaxon
Refractivity119.99 m3·mol-1Chemaxon
Polarizability49.01 Å3Chemaxon
Number of Rings2Chemaxon
Bioavailability0Chemaxon
Rule of FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9023
Blood Brain Barrier+0.8905
Caco-2 permeable-0.6281
P-glycoprotein substrateSubstrate0.7113
P-glycoprotein inhibitor INon-inhibitor0.5465
P-glycoprotein inhibitor IINon-inhibitor0.896
Renal organic cation transporterNon-inhibitor0.8273
CYP450 2C9 substrateNon-substrate0.9234
CYP450 2D6 substrateNon-substrate0.8305
CYP450 3A4 substrateSubstrate0.5584
CYP450 1A2 substrateNon-inhibitor0.7508
CYP450 2C9 inhibitorNon-inhibitor0.725
CYP450 2D6 inhibitorNon-inhibitor0.7985
CYP450 2C19 inhibitorNon-inhibitor0.7005
CYP450 3A4 inhibitorNon-inhibitor0.7139
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8392
Ames testNon AMES toxic0.5535
CarcinogenicityNon-carcinogens0.828
BiodegradationNot ready biodegradable0.9762
Rat acute toxicity2.6261 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.6903
hERG inhibition (predictor II)Non-inhibitor0.7412
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSsplash10-0a4j-9715200000-be4793aa3b5324f2d049
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSsplash10-00b9-0291650000-bfacc10ec3119e8320f0
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0kfx-1372940000-7cb1aa4d35fd2d90d7b4
MS/MS Spectrum - , positiveLC-MS/MSsplash10-00b9-0291650000-bfacc10ec3119e8320f0
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-0f79-8339240000-8ec2d7ce12683a7c062d
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-0udi-0209340000-17dee341163265e0dde1
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-00di-1095100000-ad3fb9b10ae922731316
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0udi-4396100000-d3fbd354b47380fcbf14
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-052u-3290000000-51c76d7e7f87ddac4f21
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-0udi-0098000000-bfdd2b014f306161bac1
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-216.521551
predicted
DarkChem Lite v0.1.0
[M-H]-217.473651
predicted
DarkChem Lite v0.1.0
[M-H]-209.50208
predicted
DeepCCS 1.0 (2019)
[M+H]+217.410751
predicted
DarkChem Lite v0.1.0
[M+H]+218.034851
predicted
DarkChem Lite v0.1.0
[M+H]+211.89763
predicted
DeepCCS 1.0 (2019)
[M+Na]+216.307651
predicted
DarkChem Lite v0.1.0
[M+Na]+217.727951
predicted
DarkChem Lite v0.1.0
[M+Na]+217.81017
predicted
DeepCCS 1.0 (2019)

Targets

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insights and accelerate drug research.
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Kind
Protein
Organism
HBV-D
Pharmacological action
Yes
Actions
Other
General Function
Rna-dna hybrid ribonuclease activity
Specific Function
Multifunctional enzyme that converts the viral RNA genome into dsDNA in viral cytoplasmic capsids. This enzyme displays a DNA polymerase activity that can copy either DNA or RNA templates, and a ri...
Gene Name
P
Uniprot ID
P24024
Uniprot Name
Protein P
Molecular Weight
93588.765 Da
References
  1. Chien RN, Liaw YF: Nucleos(t)ide analogues for hepatitis B virus: strategies for long-term success. Best Pract Res Clin Gastroenterol. 2008;22(6):1081-92. doi: 10.1016/j.bpg.2008.11.003. [Article]
  2. Kock J, Baumert TF, Delaney WE 4th, Blum HE, von Weizsacker F: Inhibitory effect of adefovir and lamivudine on the initiation of hepatitis B virus infection in primary tupaia hepatocytes. Hepatology. 2003 Dec;38(6):1410-8. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Atp binding
Specific Function
Catalyzes the reversible transfer of the terminal phosphate group between ATP and AMP. Plays an important role in cellular energy homeostasis and in adenine nucleotide metabolism. Adenylate kinase ...
Gene Name
AK2
Uniprot ID
P54819
Uniprot Name
Adenylate kinase 2, mitochondrial
Molecular Weight
26477.44 Da
References
  1. Link [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Nucleoside triphosphate adenylate kinase activity
Specific Function
Involved in maintaining the homeostasis of cellular nucleotides by catalyzing the interconversion of nucleoside phosphates. Efficiently phosphorylates AMP and dAMP using ATP as phosphate donor, but...
Gene Name
AK4
Uniprot ID
P27144
Uniprot Name
Adenylate kinase 4, mitochondrial
Molecular Weight
25267.83 Da
References
  1. Link [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Ribosomal small subunit binding
Specific Function
Major role in the synthesis of nucleoside triphosphates other than ATP. The ATP gamma phosphate is transferred to the NDP beta phosphate via a ping-pong mechanism, using a phosphorylated active-sit...
Gene Name
NME1
Uniprot ID
P15531
Uniprot Name
Nucleoside diphosphate kinase A
Molecular Weight
17148.635 Da
References
  1. Link [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Transcription factor activity, sequence-specific dna binding
Specific Function
Major role in the synthesis of nucleoside triphosphates other than ATP. Negatively regulates Rho activity by interacting with AKAP13/LBC. Acts as a transcriptional activator of the MYC gene; binds ...
Gene Name
NME2
Uniprot ID
P22392
Uniprot Name
Nucleoside diphosphate kinase B
Molecular Weight
17297.935 Da
References
  1. Link [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Involved in the renal elimination of endogenous and exogenous organic anions. Functions as organic anion exchanger when the uptake of one molecule of organic anion is coupled with an efflux of one ...
Gene Name
SLC22A6
Uniprot ID
Q4U2R8
Uniprot Name
Solute carrier family 22 member 6
Molecular Weight
61815.78 Da
References
  1. Cihlar T, Ho ES: Fluorescence-based assay for the interaction of small molecules with the human renal organic anion transporter 1. Anal Biochem. 2000 Jul 15;283(1):49-55. [Article]
  2. Cihlar T, Lin DC, Pritchard JB, Fuller MD, Mendel DB, Sweet DH: The antiviral nucleotide analogs cidofovir and adefovir are novel substrates for human and rat renal organic anion transporter 1. Mol Pharmacol. 1999 Sep;56(3):570-80. [Article]
  3. Ho ES, Lin DC, Mendel DB, Cihlar T: Cytotoxicity of antiviral nucleotides adefovir and cidofovir is induced by the expression of human renal organic anion transporter 1. J Am Soc Nephrol. 2000 Mar;11(3):383-93. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Atpase activity, coupled to transmembrane movement of substances
Specific Function
May be an organic anion pump relevant to cellular detoxification.
Gene Name
ABCC4
Uniprot ID
O15439
Uniprot Name
Multidrug resistance-associated protein 4
Molecular Weight
149525.33 Da
References
  1. Schuetz JD, Connelly MC, Sun D, Paibir SG, Flynn PM, Srinivas RV, Kumar A, Fridland A: MRP4: A previously unidentified factor in resistance to nucleoside-based antiviral drugs. Nat Med. 1999 Sep;5(9):1048-51. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Organic anion transmembrane transporter activity
Specific Function
Acts as a multispecific organic anion pump which can transport nucleotide analogs.
Gene Name
ABCC5
Uniprot ID
O15440
Uniprot Name
Multidrug resistance-associated protein 5
Molecular Weight
160658.8 Da
References
  1. Wijnholds J, Mol CA, van Deemter L, de Haas M, Scheffer GL, Baas F, Beijnen JH, Scheper RJ, Hatse S, De Clercq E, Balzarini J, Borst P: Multidrug-resistance protein 5 is a multispecific organic anion transporter able to transport nucleotide analogs. Proc Natl Acad Sci U S A. 2000 Jun 20;97(13):7476-81. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Toxin transporter activity
Specific Function
Mediates potential-dependent transport of a variety of organic cations. May play a significant role in the disposition of cationic neurotoxins and neurotransmitters in the brain.
Gene Name
SLC22A3
Uniprot ID
O75751
Uniprot Name
Solute carrier family 22 member 3
Molecular Weight
61279.485 Da
References
  1. Grundemann D, Schechinger B, Rappold GA, Schomig E: Molecular identification of the corticosterone-sensitive extraneuronal catecholamine transporter. Nat Neurosci. 1998 Sep;1(5):349-51. [Article]

Drug created at June 13, 2005 13:24 / Updated at March 19, 2024 11:06