A Clinical Overview of Amdoxovir

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: Biochem Pharma; Triangle Pharmaceuticals; Gilead Sciences; RFS Pharma
Phase of Development: Phase II
(Compound details obtained from ChemIDplus Advanced¹ and NIAID Therapeutics Database²)

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).³ 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.³˒⁴

T½: The mean half-life of amdoxovir and DXG in HIV-infected subjects 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.³ (The intracellular half-life of DXG-TP has been approximated at 16 hours in activated primary human lymphocytes).⁵

Metabolism/Elimination: Urinary excretion appears to be the primary route of elimination for DXG and unchanged amdoxovir.⁶ 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 subjects receiving twice-daily oral amdoxovir with and without zidovudine for 10 days.³

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.³

Amodoxovir has demonstrated synergistic antiviral activity with zidovudine, and co-administration may potentially delay the selection of TAMs and K65R.⁷

Dosing

Amdoxovir is administered twice daily and orally.⁷˒⁸

Phase Ib/IIa (HIV-infected, not receiving antiretroviral therapy at start of study):

• Amdoxovir 500 mg twice daily, with and without zidovudine 200 mg or 300 mg.⁷

Phase IIa (treatment-experienced, failing therapy at start of study):

• Amdoxovir 300 mg or 500 mg twice daily compared with tenofovir DF 300 mg once daily, each in combination with zidovudine 300 mg twice daily plus a third drug (the third drug will initially be a failing drug, and then will be lopinavir/ritonavir 400 mg/100 mg twice daily after Week 2).⁸

Adverse Events

The major toxicity of amdoxovir at high doses, as indicated by previous animal toxicology studies, was obstructive nephropathy.⁷ Non-gradable lens opacities have also been noted in a previous Phase I/II study in humans.⁷˒⁹

In a 10-day Phase Ib/IIa proof-of-concept study evaluating twice-daily amdoxovir 500 mg with and without standard-dose zidovudine and reduced-dose zidovudine, 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 subjects 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.⁷˒¹⁰

Drug Interactions

There are no apparent statistically significant drug interactions between amdoxovir and zidovudine.³˒¹⁰

References

1. United States National Library of Medicine. ChemIDplus Advanced.

2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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. Last accessed May 17, 2013.

9. 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.

10. 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. Poster presented at: 15th Conference on Retroviruses and Opportunistic Infections (CROI); February 3-6, 2008; Boston, MA. Poster 794.