Summary

Name:

Retrovir®

Synonyms:

Zidovudine; Azidothymidine; AZT; BW A509U; Zydowin

Sponsor:

GlaxoSmithKline (GSK; global presence)

Type of product:

Inhibitor

Viral family:

Retroviridae

Status:

Market
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:GlaxoSmithKline (GSK; global presence)       Type of product:Inhibitor       Mode of action:NRTI       Viral family:Retroviridae       Virus:HIV (Human Immunodeficiency virus)      

Details

Characteristics:
Small molecule, inhibitor of HIV RT enzyme;
Converted to active drug AZT-triphosphate by cell enzymes;
 
 
Inhibits viral RT by competing with natural substrate deoxythymidine triphosphate and by incorporation into nascent viral DNA, effectively blocking chain elongation;
 
 
Most affected cell enzymes are 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 syrup

 

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)
 
 
Other mutations associated with decreased sensitivity to AZT have since been identified and belong to a pattern of mutations generally common to thymidine analogues (thymidine analogue mutations, TAMs);
These include mutations at at codons 41, 67, 70, 210, 215 and 219 of the viral RT enzyme
 
Primer unblocking mechanism 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)

 

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
Approved for market in US (Mar. 19, 1987) and other markets

Remarks

NRTI;
Nucleoside analogue of pyrimidine (thymidine);
 
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