Summary

Name:

Retrovir®

Synonyms:

Zidovudine; Azidothymidine; AZT; BW A509U; Zydowin

Sponsor:

GSK (GlaxoSmithKline; Glaxo Wellcome) (global presence)

Type of product:

Inhibitor

Viral family:

Retroviridae

Status:

Market / Licensed for use
Approved for market in US (Mar. 19, 1987) and other markets

Structure

Structure Retrovir C10H13N5O4

Formula:

C10H13N5O4

Molecular weight:

267.24

Retrovir® 

Synonyms:Zidovudine; Azidothymidine; AZT; BW A509U; Zydowin       Sponsor:GSK (GlaxoSmithKline; Glaxo Wellcome) (global presence)       Type of product:Inhibitor       Mode of action:RT Inhibitor: Nucleoside or Nucleotide (including NRTI, NRTTI and NcRTI Inhibitors)       Viral family:Retroviridae       Virus:HIV-1 (Human Immunodeficiency virus)      

Details

Characteristics:
Small molecule, acting as inhibitor of HIV reverse transcriptase (RNA-dependent DNA polymerase, RT) enzyme and blocking viral replication cycle;
Converted to active drug AZT-triphosphate by cell enzymes;
   
Initially developed for use in oncology, but repositioned for use as potential treatment for HIV/AIDS;
Represents the first cpnd with demonstrated clinical activity against HIV-1, showing reduction of viral load in HIV-infected pts;
     
Inhibits HIV RT enzyme by competing with natural substrate deoxythymidine triphosphate and by incorporation into nascent viral DNA, effectively blocking chain elongation;
    
The cpnd can also inhibit cellular enzymes to a certain extent, with most affected cell enzymes being DNA polymerase α and mitochondrial DNA polymerase γ
 
 
Ref.: Mitsuya H et al., Proc Natl Acad Sci U S A. 1985 Oct;82(20):7096-100 (www.ncbi.nlm.nih.gov/pubmed/2413459); Furman PA et al., Proc Natl Acad Sci U S A. 1986 Nov;83(21):8333-7 (www.ncbi.nlm.nih.gov/pubmed/2430286); Nakashima H et al., Antimicrob Agents Chemother. 1986 Dec;30(6):933-7 (www.ncbi.nlm.nih.gov/pubmed/2434024); DeHovitz JA. N Y State J Med. 1987 Jan;87(1):7-8 (www.ncbi.nlm.nih.gov/pubmed/3470654)
   
PK Data, Dosage or Route of Administration:
Main metabolic pathway through glucuronidation in liver;
Oral bioavailability approx. 65%, with CNS and placenta penetration;
Low level of binding to plasma proteins;

Can be administered with and without food;

Oral dose is 600 mg per day (adult);

Product is also available as a liquid formulation

 

Ref.: Klecker RW Jr. et al., Clin Pharmacol Ther. 1987 Apr;41(4):407-12 (www.ncbi.nlm.nih.gov/pubmed/3549120); Product's Prescription info (www.google.com/url)

 

Resistance:
One of the first study looking at viral genotypic changes associated with loss of susceptibility to AZT identified viral RT mutations Asp67Asn, Lys70Arg, Thr215Phe/Tyr and Lys219Gln;
     
Ref.: Larder & Kemp. Science. 1989 Dec 1;246(4934):1155-8 (www.ncbi.nlm.nih.gov/pubmed/2479983)
 
 
According to the International Antiviral Society-USA (IAS-USA), the main mutations in the viral RT gene associated with loss of susceptibility to Zidovudine are: M41L, D67N, K70R, L210W, T215Y/F, K219Q/E; The T215A/C/D/E/G/H/I/L/N/S/V substitutions are revertant mutations at codon 215 that confer increased risk of virologic failure of Zidovudine or Stavudine in ARV-naive pts; The T215Y mutant may emerge quickly from one of these mutations in the presence of Zidovudine or Stavudine; Mutations known to be selected by thymidine analogue–associated mutations (TAMs: M41L, D67N, K70R, L210W, T215Y/F, and K219Q/E) also confer reduced susceptibility to all currently approved NRTIs except Emtricitabine and Lamivudine (Wensing AM et al., 2019 Resistance Mutations Update Vol. 27, Issue 3, Jul/Aug 2019 [www.iasusa.org/wp-content/uploads/2019/07/2019-drug-resistance-mutations-figures.pdf]);
See also [www.iasusa];
 
Primer unblocking mechanism has been proposed to explain AZT resistance associated with RT mutant D67N/K70R/T215Y/K219Q;
 

Co-administration with 3TC has been shown to delay resistance to AZT, and resensitization to AZT has been reported in pts with strains initially resistant to AZT, further treated with 3TC

 

Ref.: Rooke R et al., AIDS. 1989 Jul;3(7):411-5 (www.ncbi.nlm.nih.gov/pubmed/2504243); Jeffries DJ. BMJ. 1989 Apr 29;298(6681):1132-3 (www.ncbi.nlm.nih.gov/pubmed/2500164); Larder BA et al., Science. 1989 Mar 31;243(4899):1731-4 (www.ncbi.nlm.nih.gov/pubmed/2467383); Richman DD. Rev Infect Dis. 1990 Jul-Aug;12 Suppl 5:S507-10; discussion S510-2. Review. (www.ncbi.nlm.nih.gov/pubmed/2201072); Stürmer M et al., Antimicrob Agents Chemother. 2003 Jan;47(1):54-61 (www.ncbi.nlm.nih.gov/pubmed/12499169)

 

Note regarding resistance to NRTIs:
The 69 insertion complex consists of a substitution at codon 69 (typically T69S) and an insertion of 2 or more amino acids (S-S, S-A, S-G, or others); Some other amino acid changes from the wild-type T at codon 69 without the insertion may be associated with broad nRTI resistance; The 69 insertion complex is associated with resistance to all NRTIs currently approved by the FDA (as of 2019) when present with 1 or more TAMs (Thymidine Analogue-Associated Mutations) at codons 41, 210, or 215;
TAMs (i.e., M41L, D67N, K70R, L210W, T215Y/F, and K219Q/E) affect all NRTIs currently approved by the US FDA other than Emtricitabine and Lamivudine, which in fact reverse the magnitude of resistance and are recommended with Tenofovir or Zidovudine in the presence of TAMs; The degree to which cross-resistance is observed depends on the specific mutations and number of mutations involved;
151 Complex (Q151M) affects all NRTIs currently approved by the US FDA except Tenofovir; Q151M is the most important mutation in the complex (i.e., the other mutations in the complex [A62V, V75I, F77L, and F116Y] in isolation may not reflect multidrug resistance)

Ref.: Wensing AM et al., 2019 Resistance Mutations Update Vol. 27, Issue 3, Jul/Aug 2019 (www.iasusa.org/wp-content/uploads/2019/07/2019-drug-resistance-mutations-figures.pdf); See also (www.iasusa)

 

In vivo and clinical data:
Side effects: initial nausea, headache, fatigue, anemia, neutropenia, neuropathy, myopathy; 
Common side effects include headache, anorexia, nausea and vomiting,
myopathy/myositis;
Most serious AZT-related side effects : anemia, leukopenia (these effects can be exacerbated with co-administration of bone marrow-suppressive and cytotoxic agents);
 
Other significant potential side effects include lactic acidosis and hepatomegaly with steatosis including fatal cases (also seen with other nucleoside analogues, alone or in combination); 
 
Induction of tumors in animals at high doses;

Positive in mutagenesis assays, and embryotoxic at high doses in animal studies

 

Ref.: Product's Prescription info (www.google.com/url)

 

The first clinical data reporting the use of AZT in pts with HIV/AIDS have been published in the mid-1980s

 

Ref.: Yarchoan R et al., Lancet. 1986 Mar 15;1(8481):575-80 (www.ncbi.nlm.nih.gov/pubmed/2869302); Yarchoan R et al., Lancet. 1987 Jan 17;1(8525):132-5 (www.ncbi.nlm.nih.gov/pubmed/2879972); Hirsch & Kaplan. Antimicrob Agents Chemother. 1987 Jun;31(6):839-43. Review. (www.ncbi.nlm.nih.gov/pubmed/3304154); Ezzell C. Nature. 1987 Apr 2-8;326(6112):430 (www.ncbi.nlm.nih.gov/pubmed/3470603); Fischl MA et al., N Engl J Med. 1987 Jul 23;317(4):185-91 (www.ncbi.nlm.nih.gov/pubmed/3299089)

 

Activity in vitro

Ki: 7 nM (enzyme inhibition)
 
EC50: 11 nM to 50 nM
 

CCIC50: 1 to 10 μM (depending on types of cells)

 

Ref.: Mitsuya H et al., Proc Natl Acad Sci U S A. 1985 Oct;82(20):7096-100 (www.ncbi.nlm.nih.gov/pubmed/2413459); Furman PA et al., Proc Natl Acad Sci U S A. 1986 Nov;83(21):8333-7 (www.ncbi.nlm.nih.gov/pubmed/2430286); Nakashima H et al., Antimicrob Agents Chemother. 1986 Dec;30(6):933-7 (www.ncbi.nlm.nih.gov/pubmed/2434024)

 

Development status

Market / Licensed for use
Approved for market in US (Mar. 19, 1987) and other markets

Remarks

Nucleoside analogue of pyrimidine (thymidine), belonging to nucleotide reverse transcriptase inhibitor (NRTI) class of antiviral drugs;
 
First ever anti-HIV drug on the market, approved by the FDA in 1987 (Ref.: Kolata G. Science. 1987 Mar 27;235(4796):1570 [www.ncbi.nlm.nih.gov/pubmed/3469754]);
 
First synthesized at the Michigan Cancer Foundation (1964);
First antiretroviral activity shown at Max Planck Institute (1974) with mouse Retrovirus in vitro;
PK and anti-HIV activity studies, including first administration to AIDS pt performed by National Cancer Institute and Duke University;
 
Patented by Burroughs-Wellcome (now part of GlaxoSmithKline) for use as HIV/AIDS drug;
 

Now approved for use in combination with other antiretroviral drugs in the treatment of HIV infection, including prevention of maternal-fetal transmission of HIV;

 
 
Other formulation approved in 1989, followed by other approbations: 1990 (dose adjustment), 1994 (prevention of perinatal transmission mother-to-child);
 
Generic versions of Zidovudine produced by Ranbaxy Laboratories (July 2005), Aurobindo Pharma (Sept. 2005), and Roxane Laboratories have been FDA-approved in 2005 for US market and other countries, with emphasis on developing countries where they would be available for purchase under US PEPFAR plan;
 
 

On June 30, 2006, FDA granted tentative approval to fixed-dose tablet containing generic Zidovudine, Lamivudine and Nevirapine made by Aurobindo;

AZT is also sold under name Zydowin by Zydus Biogen;

Other generic versions have reached market in several countries

Patent infos

All patents for AZT as anti-HIV drug expired in 2005:

US Patent 4724232, exp. date Sept. 17, 2005
US Patent 4818538, exp. date Sept. 17, 2005
US Patent 4828838, exp. date Sept. 17, 2005
US Patent 4833130, exp. date Sept. 17, 2005
US Patent 4837208, exp. date Sept. 17, 2005


Formula: C10H13N5O4
Molecular weight: 267.24