skip navigation

Skip Nav

AIDSinfo Drug Database

AIDSinfo Drugs

Drugs by class

FDA-approved

Investigational

Amdoxovir  Audio icon

Other Names: AMDX, DAPD, prodrug of DXG
Drug Class: Nucleoside Reverse Transcriptase Inhibitors
Molecular Formula: C9 H12 N6 O3
Registry Number: 145514-04-1 (CAS)
Chemical Name: [(2R,4R)-4-(2,6-diaminopurin-9-yl)-1,3-dioxolan-2-yl]methanol
Chemical Class: Purine Nucleosides
Company: RFS Pharma
Phase of Development: IIa (discontinued)
Print

Chemical Image:
Click image to enlarge
amdoxovir
amdoxovir
Molecular Weight: 252.2328
(Compound details obtained from ChemIDplus Advanced,1 NIAID Therapeutics Database,2 ClinicalTrials.gov,3 and HIV i-BASE/Treatment Action Group 2013 Pipeline Report4)
 
Patent Version Content

NOTE: The development of amdoxovir for HIV treatment has been discontinued.


The study of amdoxovir as an NRTI HIV medicine was discontinued. The last clinical trial activity involving amdoxovir appears to have been in 2010.4


Pharmacology


Mechanism of Action: NRTI. Amdoxovir, a guanosine nucleoside analog, is a prodrug deaminated by adenosine deaminase to 9-(β-D-1,3-dioxolan-4-yl)guanine (DXG).5 DXG is phosphorylated to its active triphosphate metabolite (DXG-TP), which inhibits the activity of HIV-1 reverse transcriptase by competing with natural substrates and then causing DNA chain termination after incorporation into viral DNA. DXG-TP has exhibited activity against HBV in human hepatocytes.5,6 

Half-life (T½): The mean half-life of amdoxovir and DXG in HIV-infected participants receiving twice-daily oral amdoxovir with and without zidovudine ranged from 1.3 to 1.6 hours for amdoxovir and from 2.5 to 2.9 hours for DXG on Day 1 of dosing. A longer half-life of decay for DXG on Day 10 (steady-state) was evident after 12 hours postdosing.5 (The intracellular half-life of DXG-TP has been approximated at 16 hours in activated primary human lymphocytes).7

Metabolism/Elimination: Urinary excretion appears to be the primary route of elimination for DXG and unchanged amdoxovir.8 The percentage of amdoxovir recovered in urine in 1 dose interval at steady-state was 1.1% to 3.9 % as amdoxovir and 25.3% to 27.7% as DXG in HIV-infected participants receiving twice-daily oral amdoxovir with and without zidovudine for 10 days.5

Resistance: Amdoxovir has demonstrated in vitro activity against viruses containing M184V/I, certain thymidine analog mutations (TAMs: M41L, D67N, K70R, L210W, T215Y/F, and K219Q/E), and the 69SS double insert. Resistance has been associated with K65R or L74V mutations.5

Amodoxovir has demonstrated synergistic antiviral activity with zidovudine, and coadministration may potentially delay the selection of TAMs and K65R.9


Clinical Trials


Study Identifiers: RFS-AMDX-203; NCT00432016
Sponsor: RFS Pharma, LLC
Phase: Ib/IIa
Study Purpose: The purpose of this proof-of-concept study was to evaluate the safety and antiviral activity of amdoxovir in combination with 2 different doses of zidovudine over 10 days.
Study Population: Participants were HIV-infected, treatment-naive or –experienced (no ART within 90 days of screening) adults with HIV RNA ≥5,000 copies/mL and CD4 counts ≥200 cells/mm3.
Dosing: Participants were assigned to 1 of the following 3 groups:

  • Amdoxovir 500 mg or placebo, twice daily
  • Amdoxovir 500 mg or placebo, each in combination with zidovudine 300 mg, twice daily
  • Amdoxovir 500 mg or placebo, each in combination with zidovudine 200 mg, twice daily9-11

Selected Study Results:

 

Study Identifiers: RFSP-AMDX-2010; NCT01737359
Phase: IIa
Study Purpose: The purpose of this study was to compare the safety and efficacy of 2 different doses of amdoxovir to the safety and efficacy of tenofovir DF. Amdoxovir and tenofovir DF were combined with zidovudine plus lopinavir/ritonavir over 12 weeks.
Study Population:

  • Participants were treatment-experienced adults who were infected with HIV containing the M184I/V mutation in addition to 0-2 TAMs and who were failing their ART regimen.
  • Participants had HIV RNA ≥2,000 copies/mL.

Dosing: Participants were assigned to 1 of the following 3 groups:

  • Amdoxovir 300 mg twice daily + zidovudine 300 mg twice daily + a failing third drug. After Week 2, the failing third drug was replaced with lopinavir/ritonavir 400 mg/100 mg twice daily.
  • Amdoxovir 500 mg twice daily + zidovudine 300 mg twice daily + a failing third drug. After Week 2, the failing third drug was replaced with lopinavir/ritonavir 400 mg/100 mg twice daily.
  • Tenofovir DF 300 mg once daily + zidovudine 300 mg twice daily + a failing third drug. After Week 2, the failing third drug was replaced with lopinavir/ritonavir 400 mg/100 mg twice daily.3

* This study was terminated.3 A 36-week extension study (NCT01738555) to RFSP-AMDX-2010 was previously planned but was withdrawn prior to study enrollment.12
 
Other HIV-related studies involving amdoxovir have also been completed.


Adverse Events


The major toxicity of amdoxovir at high doses, as indicated by previous animal toxicology studies, was obstructive nephropathy.9 Non-gradable lens opacities have also been noted in a previous Phase I/II study in humans.9,13

In RFS-AMDX-203 (NCT00432016), treatment was well tolerated, with no study discontinuations or serious adverse events (SAEs) reported. Adverse events (AEs) were mild to moderate in severity and were transient. The most frequently occurring AEs in participants receiving amdoxovir in combination with zidovudine were headache and nausea. There were no clinically significant changes in biochemistry, hematological, or urinalysis parameters studied. There were no clinically relevant changes in hemoglobin or mean corpuscular volume.9,11


Drug Interactions


There are no apparent statistically significant drug interactions between amdoxovir and zidovudine.5,11


References


  1. United States National Library of Medicine. ChemIDplus Advanced. Available at: http://chem.sis.nlm.nih.gov/chemidplus/rn/145514-04-1. Last accessed on January 24, 2017.
  2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. Available at: http://chemdb.niaid.nih.gov/DrugDevelopmentHIV.aspx. Last accessed on January 24, 2017.
  3. RFS Pharma, LLC. A Phase IIa, Randomized, Double-blind, Active-controlled, 12-week Study of Amdoxovir (Two Doses) Versus Tenofovir DF, in Combination With Zidovudine in HIV-1 Treatment-experienced Subjects With M184I/V Mutation in Addition to 0-2 Confirmed Thymidine Analog Mutations. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on November 27, 2012. NLM Identifier: NCT01737359. Available at: http://www.clinicaltrials.gov/ct2/show/NCT01737359. Last accessed on January 24, 2017.
  4. Clayden P, Collins S, Daniels C, et al. HIV i-BASE/Treatment Action Group. 2013 Pipeline Report. Benzacar A, ed. June 2013. Available at: http://www.treatmentactiongroup.org/sites/default/files/201306/2013%20Pipeline%20Report.pdf. Last accessed on January 24, 2017.
  5. Hurwitz SJ, Asif G, Fromentin E, Tharnish PM, Schinazi RF. Lack of Pharmacokinetic Interaction between Amdoxovir and Reduced- and Standard-Dose Zidovudine in HIV-1-Infected Individuals. Antimicrob Agents Chemother. 2010 Mar;54(3):1248-55. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2826005/. Last accessed on January 24, 2017.
  6. Herman BD and Sluis-Cremer N. Molecular Pharmacology of Nucleoside and Nucleotide HIV-1 Reverse Transcriptase Inhibitors. In: Gallelli L, ed. Pharmacology. In Tech, DOI: 10.5772/32969; 2012: p 63-80. Available at: http://www.intechopen.com/books/pharmacology/molecular-pharmacology-of-nucleoside-and-nucleotide-hiv-1-reverse-transcriptase-inhibitors. Last accessed on January 24, 2017.
  7. Hernandez-Santiago BI, Obikhod A, Fromentin E, Hurwitz SJ, Schinazi RF. Short communication cellular pharmacology of 9-(beta-D-1,3-dioxolan-4-yl) guanine and its lack of drug interactions with zidovudine in primary human lymphocytes. Antivir Chem Chemother. 2007;18(6):343-6. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18320938. Last accessed on January 24, 2017.
  8. Wang LH, Bigley JW, Brosnan-Cook M, Sista ND, Rousseau F, DAPD-101 Clinical Trial Group. The Disposition of DAPD and Its Active Metabolite DXG in Therapy Naïve and Experienced HIV-Infected Subjects. Poster presented at: 8th Conference on Retroviruses and Opportunistic Infections (CROI); February 4-8, 2001; Chicago, IL. Poster 752. Available at: http://croi.net/2001/posters/752.pdf. Last accessed on May 30, 2013.
  9. Murphy RL, Kivel NM, Zala C, et al. Antiviral activity and tolerability of amdoxovir with zidovudine in a randomized double-blind placebo-controlled study in HIV-1-infected individuals. Antivir Ther. 2010;15(2):185-92. Available at: http://www.intmedpress.com/serveFile.cfm?sUID=c012fd04-d7b4-4a7f-8c82-c772579b039a. Last accessed on January 24, 2017.
  10. RFS Pharma, LLC. A Randomized, Placebo-Controlled Study to Evaluate Safety, Tolerance, Pharmacokinetics and Antiviral Activity of Amdoxovir and Zidovudine in Untreated HIV-1 Infected Subjects Currently Untreated. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on February 5, 2007. NLM Identifier: NCT00432016. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00432016. Last accessed on January 24, 2017.
  11. Murphy R, Zala C, Ochoa C, et al. Pharmacokinetics and Potent Anti-HIV-1 Activity of Amdoxovir Plus Zidovudine in a Randomized Double-blind Placebo-controlled Study. 15th Conference on Retroviruses and Opportunistic Infections (CROI); February 3-6, 2008; Boston, MA. Levin: Conference reports for National AIDS Treatment Advocacy Project (NATAP); 2008. Available at: http://www.natap.org/2008/CROI/croi_96.htm. Last accessed on January 24, 2017.
  12. RFS Pharma, LLC.  An Open-label, 36-week Extension Study on Amdoxovir at 500 mg Bid or 300 mg Bid in Combination With Zidovudine and Lopinavir/Ritonavir in HIV-1 Treatment-experienced Subjects With M184I/V Mutation in Addition to 0-2 Confirmed Thymidine Analog Mutations. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on November 28, 2012. NLM Identifier: NCT01738555. Available at: http://clinicaltrials.gov/show/NCT01738555. Last accessed on January 24, 2017.
  13. Thompson M, Richmond G, Kessler H, et al.  Preliminary Results of Dosing of Amdoxovir in Treatment-experienced Patients. Paper presented at: 10th Conference on Retroviruses and Opportunistic Infections (CROI); February 10-14, 2003; Boston, MA. Paper 554. Available at: http://www.retroconference.org/2003/cd/Abstract/554.htm. Last accessed on May 30, 2013.


Last Reviewed: January 24, 2017

Back to Top