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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: Phase II
Chemical Image:
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amdoxovir
amdoxovir
Molecular Weight: 252.233
(Compound details obtained from ChemIDplus Advanced,1 NIAID Therapeutics Database,2 and RFS Pharma, LLC press release3)
Patent Version Content

Pharmacology


Mechanism of Action: Nucleoside reverse transcriptase inhibitor. Amdoxovir, a guanosine nucleoside analog, is a prodrug deaminated by adenosine deaminase to 9-(β-D-1,3-dioxolan-4-yl)guanine (DXG).4 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 causing DNA chain termination after incorporation into viral DNA. DXG-TP has exhibited activity against hepatitis B virus (HBV) in human hepatocytes.4,5

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.4 (The intracellular half-life of DXG-TP has been approximated at 16 hours in activated primary human lymphocytes).6

Metabolism/Elimination: Urinary excretion appears to be the primary route of elimination for DXG and unchanged amdoxovir.7 The percentage of amdoxovir recovered in urine in one 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.4

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.4

Amodoxovir has demonstrated synergistic antiviral activity with zidovudine, and co-administration may potentially delay the selection of TAMs and K65R.8


Dosing in Clinical Trials


Study Identifiers: RFS-AMDX-203; NCT004320169
Phase: Ib/IIa
Study Purpose: Proof-of-concept study to evaluate the safety and antiviral activity of amdoxovir in combination with two different doses of zidovudine over 10 days
Study Population: HIV-infected, treatment-naive or –experienced (no antiretroviral therapy [ART] within 90 days of screening) adults
Dosing: Participants were assigned to one of the following three 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 daily.8,9
(See references cited above for information on study results.)


Study Identifiers
: RFSP-AMDX-2010; NCT0173735910
Phase: IIa
Study Purpose: Study to evaluate the safety and efficacy of two different doses of amdoxovir versus tenofovir DF, each combined with zidovudine plus lopinavir/ritonavir over 12 weeks
Study Population: HIV-infected, treatment-experienced adults who are currently failing ART and are infected with HIV containing the M184I/V mutation in addition to 0-2 TAMs
Dosing: Participants were assigned to one of the following three groups:

  • Amdoxovir 300 mg twice daily in combination with zidovudine 300 mg twice daily plus 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 in combination with zidovudine 300 mg twice daily plus 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 in combination with zidovudine 300 mg twice daily plus a failing third drug. After Week 2, the failing third drug was replaced with lopinavir/ritonavir 400 mg/100 mg twice daily.10
* A 36-week extension study of RFSP-AMDX-2010 was previously planned, but it was withdrawn prior to study enrollment.11


Adverse Events


The major toxicity of amdoxovir at high doses, as indicated by previous animal toxicology studies, was obstructive nephropathy.8 Non-gradable lens opacities have also been noted in a previous Phase I/II study in humans.8,12

In RFS-AMDX-203, treatment was well tolerated, with no study discontinuations or serious adverse events reported. Adverse events were mild to moderate in severity and were transient. The most frequently occurring adverse events 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.8,13


Drug Interactions


There are no apparent statistically significant drug interactions between amdoxovir and zidovudine.4,13


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 October 29, 2014.
  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 October 29, 2014.
  3. RFS Pharma, LLC: Press Release, dated November 15, 2010. RFS Pharma Awarded Therapeutic Tax Credit and Announces the Approval by the U.S. FDA to Initiate a Phase 2 Study on the Anti-HIV drug Amdoxovir. Available at: http://www.rfspharma.com/images/Press_Release_RFSP_November_15_2010.pdf. Last accessed on October 29, 2014.
  4. 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 October 29, 2014.
  5. 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 October 29, 2014.
  6. 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 October 29, 2014.
  7. 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.
  8. 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 October 29, 2014.
  9. 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 October 29, 2014.
  10. 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 October 29, 2014.
  11. 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 October 29, 2014.
  12. 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.
  13. 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 October 29, 2014.
     
 


Last Reviewed: October 29, 2014

Last Updated: October 29, 2014


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