Drug Information

Drug (ID: DG00008) and It's Reported Resistant Information

• Name: Adefovir
• Synonyms: ADEFOVIR; 106941-25-7; PMEA; ((2-(6-Amino-9H-purin-9-yl)ethoxy)methyl)phosphonic acid; 9-(2-Phosphonylmethoxyethyl)adenine; GS-0393; GS 0393; GS 393; 9-(2-(Phosphonomethoxy)ethyl)adenine; N-(2-Phosphonylmethoxyethyl)adenine; DRG-0156; UNII-6GQP90I798; C8H12N5O4P; HSDB 8079; CHEMBL484; 2-(6-aminopurin-9-yl)ethoxymethylphosphonic acid; BRN 3561094; {[2-(6-Amino-9h-Purin-9-Yl)ethoxy]methyl}phosphonic Acid; N-(2-Phophonomethoxyethyl-2,6-diaminopurine); Phosphonic acid, [[2-(6-amino-9H-purin-9-yl)ethoxy]methyl]-; 6GQP90I798
• Indication:
  In total 1 Indication(s)
  Discovery agent [ICD-11: N.A.]; Investigative; [1], [2], [3]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (2 diseases)
  Glaucoma [ICD-11: 9C61]; [4]
  Hepatitis B viral hepatitis [ICD-11: 1E51]; [1], [2], [3]
  Disease(s) with Resistance Information Validated by in-vivo Model for This Drug (1 diseases)
  Hepatitis B viral hepatitis [ICD-11: 1E51]; [5]
• Target: Herpes simplex virus DNA polymerase UL30 (HSV UL30); DPOL_HHV11; [1]
• Formula: C8H12N5O4P
• IsoSMILES: C1=NC(=C2C(=N1)N(C=N2)CCOCP(=O)(O)O)N
• InChI: 1S/C8H12N5O4P/c9-7-6-8(11-3-10-7)13(4-12-6)1-2-17-5-18(14,15)16/h3-4H,1-2,5H2,(H2,9,10,11)(H2,14,15,16)
• InChIKey: SUPKOOSCJHTBAH-UHFFFAOYSA-N
• PubChem CID: 60172
• ChEBI ID: CHEBI:2469
• TTD Drug ID: D00UUM
• VARIDT ID: DR00015
• DrugBank ID: DB13868

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  IDUE: Irregularity in Drug Uptake and Drug Efflux

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-01: Infectious/parasitic diseases

Hepatitis B viral hepatitis [ICD-11: 1E51]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: HBV Polymerase/reverse transcriptase domain (HBV RT) [1], [2], [3]

• Molecule Alteration: Missense mutation; p.A181T
• Resistant Disease: Hepatitis B virus infection [ICD-11: 1E51.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: HBV genotyping and sequencing assay
• Experiment for Drug Resistance: Pathological response evaluation assay
• Mechanism Description: The primary resistance mutations in the RT region at sites 169, 180, 181, 184, 202, 204, 236 and 250 have been shown to be involved in cross-resistance to anti-HBV agents via four pathways of viral evolution based on the different structures of the five NAs.

Key Molecule: HBV Polymerase/reverse transcriptase domain (HBV RT) [1], [2], [3]

• Molecule Alteration: Missense mutation; p.A181V
• Resistant Disease: Hepatitis B virus infection [ICD-11: 1E51.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: HBV genotyping and sequencing assay
• Experiment for Drug Resistance: Pathological response evaluation assay
• Mechanism Description: The primary resistance mutations in the RT region at sites 169, 180, 181, 184, 202, 204, 236 and 250 have been shown to be involved in cross-resistance to anti-HBV agents via four pathways of viral evolution based on the different structures of the five NAs.

Key Molecule: HBV Polymerase/reverse transcriptase domain (HBV RT) [1], [2], [3]

• Molecule Alteration: Missense mutation; p.N236T
• Resistant Disease: Hepatitis B virus infection [ICD-11: 1E51.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: HBV genotyping and sequencing assay
• Experiment for Drug Resistance: Pathological response evaluation assay
• Mechanism Description: The primary resistance mutations in the RT region at sites 169, 180, 181, 184, 202, 204, 236 and 250 have been shown to be involved in cross-resistance to anti-HBV agents via four pathways of viral evolution based on the different structures of the five NAs.

Key Molecule: HBV Polymerase/reverse transcriptase domain (HBV RT) [1], [2], [3]

• Molecule Alteration: Missense mutation; p.A181T+p.N236T
• Resistant Disease: Hepatitis B virus infection [ICD-11: 1E51.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: HBV genotyping and sequencing assay
• Experiment for Drug Resistance: Pathological response evaluation assay
• Mechanism Description: The primary resistance mutations in the RT region at sites 169, 180, 181, 184, 202, 204, 236 and 250 have been shown to be involved in cross-resistance to anti-HBV agents via four pathways of viral evolution based on the different structures of the five NAs.

Key Molecule: HBV Polymerase/reverse transcriptase domain (HBV RT) [1], [2], [3]

• Molecule Alteration: Missense mutation; p.A181V+p.N236T
• Resistant Disease: Hepatitis B virus infection [ICD-11: 1E51.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: HBV genotyping and sequencing assay
• Experiment for Drug Resistance: Pathological response evaluation assay
• Mechanism Description: The primary resistance mutations in the RT region at sites 169, 180, 181, 184, 202, 204, 236 and 250 have been shown to be involved in cross-resistance to anti-HBV agents via four pathways of viral evolution based on the different structures of the five NAs.

Key Molecule: HBV Polymerase/reverse transcriptase domain (HBV RT) [5]

• Molecule Alteration: Missense mutation; rtN236T+ rtA181V+ rtA181T
• Resistant Disease: Hepatitis B virus infection [ICD-11: 1E51.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• Mechanism Description: The common LMV substitution for primary resistance involves the amino acid change rtM204V/I arising in the YMDD, a catalytic motif of pol. The compensatory change associated with rtM204V is at rtL180M, rtV173L and rtL80M. ADV resistance is characterized by rtN236T and/or rtA181V/T. ETV resistance tends to emerge in a stepwise manner with the rtS202I change occurring sequentially in viruses already bearing LMV resistance substitution (rtL180M plus rtM204V) mutations, although primary ETV resistance has been reported where these mutations have appeared simultaneously. For LdT, the year 2 resistance rates were 29% in HBeAg-positive and 11% in HBeAg-negative patients with the primary resistance mutation rtM204I. Secondary mutations associated with antiviral therapy, namely rtL80I/V and rtV173L plus rtL180M can also accompany this signature mutation in approximately 2-5% of cases. No definitive TDF-associated mutations have been described in treatment-naive patients taking TDF for up 5 years, but the selection of ADV-therapy associated resistance mutations, rtA181T/V and rtN236T, leads to reduced sensitivity to TDF when the patient is switched, and this has been described in both the clinical and virological setting.

ICD-09: Visual system diseases

Glaucoma [ICD-11: 9C61]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family C5 (ABCC5) [4]

• Molecule Alteration: Expression; Regulation
• Resistant Disease: Glaucoma [ICD-11: 9C61.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SIRC cells; Colon; Homo sapiens (Human); CVCL_2724
• In Vitro Model: SV40-HCEC cells; Kidney; Homo sapiens (Human); CVCL_1272
• Experiment for Molecule Alteration: RT-PCR; Immunoprecipitation assay; Western blot analysis; Immunostaining assay
• Experiment for Drug Resistance: Trypan blue exclusion test assay
• Mechanism Description: Taken together immunolocalization on human cornea, in vitro efflux in human, rabbit corneal and MRP5 over expressing cells, ex vivo and in vivo studies in intact rabbit cornea suggest that MRP5 on cornea can significantly lower the permeability of antiviral and glaucoma drugs.

Key Molecule: ATP-binding cassette sub-family C5 (ABCC5) [4]

• Molecule Alteration: Expression; Regulation
• Resistant Disease: Glaucoma [ICD-11: 9C61.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SIRC cells; Colon; Homo sapiens (Human); CVCL_2724
• In Vitro Model: SV40-HCEC cells; Kidney; Homo sapiens (Human); CVCL_1272
• Experiment for Molecule Alteration: RT-PCR; Immunoprecipitation assay; Western blot analysis; Immunostaining assay
• Experiment for Drug Resistance: Trypan blue exclusion test assay
• Mechanism Description: Taken together immunolocalization on human cornea, in vitro efflux in human, rabbit corneal and MRP5 over expressing cells, ex vivo and in vivo studies in intact rabbit cornea suggest that MRP5 on cornea can significantly lower the permeability of antiviral and glaucoma drugs.

References

• Ref 1: HBVdb: a knowledge database for Hepatitis B Virus. Nucleic Acids Res. 2013 Jan;41(Database issue):D566-70. doi: 10.1093/nar/gks1022. Epub 2012 Nov 3.
• Ref 2: Estimations of worldwide prevalence of chronic hepatitis B virus infection: a systematic review of data published between 1965 and 2013. Lancet. 2015 Oct 17;386(10003):1546-55. doi: 10.1016/S0140-6736(15)61412-X. Epub 2015 Jul 28.
• Ref 3: Trends in hepatitis B virus resistance to nucleoside/nucleotide analogues in North China from 2009-2016: A retrospective study. Int J Antimicrob Agents. 2018 Aug;52(2):201-209. doi: 10.1016/j.ijantimicag.2018.04.002. Epub 2018 Apr 12.
• Ref 4: Expression of multidrug resistance associated protein 5 (MRP5) on cornea and its role in drug efflux .J Ocul Pharmacol Ther. 2009 Apr;25(2):121-32. doi: 10.1089/jop.2008.0084. 10.1089/jop.2008.0084
• Ref 5: Hepatitis B antivirals and resistance .Curr Opin Virol. 2013 Oct;3(5):495-500. doi: 10.1016/j.coviro.2013.08.006. Epub 2013 Sep 7. 10.1016/j.coviro.2013.08.006