Apricitabine

Last updated
Apricitabine
Apricitabine.svg
Clinical data
Routes of
administration 		Oral
ATC code
  • none
Legal status
Legal status
  • Investigational
Pharmacokinetic data
Bioavailability 65 to 80%
Protein binding < 4%
Metabolism To apricitabine triphosphate
Elimination half-life 6 to 7 hours (triphosphate)
Excretion Renal
Identifiers
  • 4-amino-1-[(2R,4R)-2-(hydroxymethyl)-1,3- oxathiolan-4-yl]pyrimidin-2(1H)-one
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C8H11N3O3S
Molar mass 229.25 g·mol−1
3D model (JSmol)
  • O=C1/N=C(/N)\C=C/N1[C@@H]2S[C@@H](OC2)CO
  • InChI=1S/C8H11N3O3S/c9-5-1-2-11(8(13)10-5)6-4-14-7(3-12)15-6/h1-2,6-7,12H,3-4H2,(H2,9,10,13)/t6-,7-/m1/s1 Yes check.svgY
  • Key:RYMCFYKJDVMSIR-RNFRBKRXSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Apricitabine (INN, codenamed AVX754 and SPD754, sometimes abbreviated to ATC) is an experimental nucleoside reverse transcriptase inhibitor (NRTI) against HIV. It is structurally related to lamivudine and emtricitabine, and, like these, is an analogue of cytidine.

Contents

History

It was first developed by BioChem Pharma (where it was called BCH10618). BioChem Pharma was then sold to Shire Pharmaceuticals (where apricitabine was called SPD754). Shire then sold the rights to develop the drug to Avexa Pharmaceuticals, an Australian pharmaceutical company. [1] As of 2009, apricitabine has closed its phase III clinical trial, [2] and has been granted fast track status by the United States Food and Drug Administration. [3]

Avexa announced its decision to end work on apricitabine in May 2010, which Avexa spent more than A$100 million ($90 million) developing and was in the final of three stages of patient studies usually needed for U.S. regulatory approval. Grounds for the shutdown included the inability to find commercial partners for global licensing, concerns about legal protections of the drug in the US market, and difficulty confirming the effectiveness of the drug in patients where other retroviral drugs masked key indicators. [4]

In March 2011 it was announced by the company to the Australian Stock Exchange that the FDA had agreed that a new, shorter, single Phase III trial design, including about 300 patients dosed for 2 weeks, was required before approval. A similar agreement with the EMA was announced in March 2012. [5]

In November 2011 the company sought to extend its patents over apricitabine and was in discussions for fast-track approval with European regulators. The company also indicated that clinical trials had shown better-than-expected results from simultaneous provision of the drug alongside two other marketed drugs when compared to those drugs with lamivudine, another NRTI. [6]

Avexa's latest update in 2013 reported that the drug was still in phase IIb trials and had not yet started phase III. [7]

Dosage

As a monotherapy, 1200 mg apricitabine per day reduced the viral load by up to 1.65 logs (45 fold) in a small, 10-day randomized controlled trial. [8] An 800 mg dose twice a day is being used in later studies.

Adverse effects

Apricitabine appears to be well tolerated. The most common side effects associated with its use were headache (although there was no significant difference between participants who took apricitabine and those given a placebo), nasal congestion, and muscle pain. [8] In a six-month trial, common adverse effects were nausea, diarrhea, elevated blood levels of triglycerides, and upper respiratory infection—similar to those of lamivudine; apricitabine was not associated with abnormal lipase levels, bone marrow suppression, or liver and kidney toxicity. [9] No patients in either study had to stop taking apricitabine because of side effects.

Drug resistance

In vitro, apricitabine is effective against NRTI-(lamivudine and zidovudine)-resistant virus strains, including M184V and multiple thymidine analogue mutations (TAMs).

In early studies, no mutations causing drug resistance were observed. Newer trials showed that apricitabine may induce K65R mutations, resulting in resistance against didanosine and tenofovir. [1]

In clinical studies, apricitabine has been good at reducing viral loads while apparently producing little selection pressure, resulting in the addition of no further mutations in treatment-experienced patients with common pre-existing mutations, including M184V or K65R or TAMs (M41L, M184V, and T215Y). [10]

Related Research Articles

<span class="mw-page-title-main">Zidovudine</span> Antiretroviral medication

Zidovudine (ZDV), also known as azidothymidine (AZT), was the first antiretroviral medication used to prevent and treat HIV/AIDS. It is generally recommended for use in combination with other antiretrovirals. It may be used to prevent mother-to-child spread during birth or after a needlestick injury or other potential exposure. It is sold both by itself and together as lamivudine/zidovudine and abacavir/lamivudine/zidovudine. It can be used by mouth or by slow injection into a vein.

The management of HIV/AIDS normally includes the use of multiple antiretroviral drugs as a strategy to control HIV infection. There are several classes of antiretroviral agents that act on different stages of the HIV life-cycle. The use of multiple drugs that act on different viral targets is known as highly active antiretroviral therapy (HAART). HAART decreases the patient's total burden of HIV, maintains function of the immune system, and prevents opportunistic infections that often lead to death. HAART also prevents the transmission of HIV between serodiscordant same-sex and opposite-sex partners so long as the HIV-positive partner maintains an undetectable viral load.

Reverse-transcriptase inhibitors (RTIs) are a class of antiretroviral drugs used to treat HIV infection or AIDS, and in some cases hepatitis B. RTIs inhibit activity of reverse transcriptase, a viral DNA polymerase that is required for replication of HIV and other retroviruses.

<span class="mw-page-title-main">Zalcitabine</span> Chemical compound

Zalcitabine, also called dideoxycytidine, is a nucleoside analog reverse-transcriptase inhibitor (NRTI) sold under the trade name Hivid. Zalcitabine was the third antiretroviral to be approved by the Food and Drug Administration (FDA) for the treatment of HIV/AIDS. It is used as part of a combination regimen.

<span class="mw-page-title-main">Stavudine</span> Chemical compound

Stavudine (d4T), sold under the brand name Zerit among others, is an antiretroviral medication used to prevent and treat HIV/AIDS. It is generally recommended for use with other antiretrovirals. It may be used for prevention after a needlestick injury or other potential exposure. However, it is not a first-line treatment. It is given by mouth.

<span class="mw-page-title-main">Lamivudine</span> Chemical compound

Lamivudine, commonly called 3TC, is an antiretroviral medication used to prevent and treat HIV/AIDS. It is also used to treat chronic hepatitis B when other options are not possible. It is effective against both HIV-1 and HIV-2. It is typically used in combination with other antiretrovirals such as zidovudine, dolutegravir, and abacavir. Lamivudine may be included as part of post-exposure prevention in those who have been potentially exposed to HIV. Lamivudine is taken by mouth as a liquid or tablet.

<span class="mw-page-title-main">Emtricitabine</span> Antiretroviral drug used to treat HIV infection

Emtricitabine, with trade name Emtriva, is a nucleoside reverse-transcriptase inhibitor (NRTI) for the prevention and treatment of HIV infection in adults and children. In 2019, it was the 494th most commonly prescribed medication in the United States, with more than 3 thousand prescriptions.

<span class="mw-page-title-main">Nevirapine</span> Chemical compound

Nevirapine (NVP), sold under the brand name Viramune among others, is a medication used to treat and prevent HIV/AIDS, specifically HIV-1. It is generally recommended for use with other antiretroviral medications. It may be used to prevent mother to child spread during birth but is not recommended following other exposures. It is taken by mouth.

Combination therapy or polytherapy is therapy that uses more than one medication or modality. Typically, the term refers to using multiple therapies to treat a single disease, and often all the therapies are pharmaceutical. 'Pharmaceutical' combination therapy may be achieved by prescribing/administering separate drugs, or, where available, dosage forms that contain more than one active ingredient.

<span class="mw-page-title-main">Entecavir</span> Chemical compound

Entecavir (ETV), sold under the brand name Baraclude, is an antiviral medication used in the treatment of hepatitis B virus (HBV) infection. In those with both HIV/AIDS and HBV antiretroviral medication should also be used. Entecavir is taken by mouth as a tablet or solution.

<span class="mw-page-title-main">Peramivir</span> Antiviral drug targeting influenza

Peramivir is an antiviral drug developed by BioCryst Pharmaceuticals for the treatment of influenza. Peramivir is a neuraminidase inhibitor, acting as a transition-state analogue inhibitor of influenza neuraminidase and thereby preventing new viruses from emerging from infected cells. It is approved for intravenous administration.

<span class="mw-page-title-main">Indinavir</span> Chemical compound

Indinavir is a protease inhibitor used as a component of highly active antiretroviral therapy to treat HIV/AIDS. It is soluble white powder administered orally in combination with other antiviral drugs. The drug prevents protease from functioning normally. Consequently, HIV viruses cannot reproduce, causing a decrease in the viral load. Commercially sold indinavir is indinavir anhydrous, which is indinavir with an additional amine in the hydroxyethylene backbone. This enhances its solubility and oral bioavailability, making it easier for users to intake. It was synthetically produced for the purpose of inhibiting the protease in the HIV virus.

<span class="mw-page-title-main">Lamivudine/zidovudine</span> Combination drug for HIV

Lamivudine/zidovudine, sold under the brand name Combivir among others, is a fixed-dose combination antiretroviral medication used to treat HIV/AIDS. It contains two antiretroviral medications, lamivudine and zidovudine. It is used together with other antiretrovirals. It is taken by mouth twice a day.

<span class="mw-page-title-main">Telbivudine</span> Chemical compound

Telbivudine is an antiviral drug used in the treatment of hepatitis B infection. It is marketed by Swiss pharmaceutical company Novartis under the trade names Sebivo and Tyzeka. Clinical trials have shown it to be significantly more effective than lamivudine or adefovir, and less likely to cause resistance. However, HBV signature resistance mutation M204I or L180M+M204V have been associated with Telbivudine resistance.

<span class="mw-page-title-main">Stampidine</span> Medication

Stampidine is an experimental nucleoside reverse transcriptase inhibitor (NRTI) with anti-HIV activity.

Non-nucleoside reverse-transcriptase inhibitors (NNRTIs) are antiretroviral drugs used in the treatment of human immunodeficiency virus (HIV). NNRTIs inhibit reverse transcriptase (RT), an enzyme that controls the replication of the genetic material of HIV. RT is one of the most popular targets in the field of antiretroviral drug development.

Discovery and development of nucleoside and nucleotide reverse-transcriptase inhibitors began in the 1980s when the AIDS epidemic hit Western societies. NRTIs inhibit the reverse transcriptase (RT), an enzyme that controls the replication of the genetic material of the human immunodeficiency virus (HIV). The first NRTI was zidovudine, approved by the U.S. Food and Drug Administration (FDA) in 1987, which was the first step towards treatment of HIV. Six NRTI agents and one NtRTI have followed. The NRTIs and the NtRTI are analogues of endogenous 2´-deoxy-nucleoside and nucleotide. Drug-resistant viruses are an inevitable consequence of prolonged exposure of HIV-1 to anti-HIV drugs.

<span class="mw-page-title-main">Icotinib</span> Chemical compound

Icotinib is a highly selective, first generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). Icotinib is approved for use in China as first-line monotherapy in patients with non-small-cell lung cancer with somatic EGFR mutations.

<span class="mw-page-title-main">Abacavir/dolutegravir/lamivudine</span> Drug combination for HIV

Abacavir/dolutegravir/lamivudine, sold under the brand name Triumeq among others, is a fixed-dose combination antiretroviral medication for the treatment of HIV/AIDS. It is a combination of three medications with different and complementary mechanisms of action: abacavir, dolutegravir and lamivudine.

Dolutegravir/lamivudine, sold under the brand name Dovato, is a fixed-dose combination antiretroviral medication for the treatment of HIV/AIDS. It contains dolutegravir, as the salt, an integrase strand transfer inhibitor (INSTI), and lamivudine, a nucleoside analogue reverse transcriptase inhibitor (NRTI). It is taken by mouth.

References

  1. 1 2 "Apricitabine". AIDSmeds.com. Archived from the original on March 21, 2008.
  2. ↑ Avexa Closes ATC's Phase III Trial To Evaluate Data
  3. ↑ "Apricitabine". AIDSinfo. U.S. National Institutes of Health. March 13, 2007. Archived from the original on June 5, 2011. Retrieved 2008-08-29.
  4. ↑ "Avexa closes apricitabine (ATC) program" (PDF). Avexa Company Announcement. Archived from the original (PDF) on August 21, 2011.
  5. ↑ "Avexa and FDA agree path forward for ATC" (PDF). Avexa. Archived from the original (PDF) on March 20, 2012.
  6. ↑ Avexa Company Announcement to Australian Stock Exchange: Avexa files to extend ATC patent life
  7. ↑ "Update on apricitabine's Clinical Development" (PDF). 2013-09-14. Archived from the original (PDF) on 2014-02-25. Retrieved 2014-04-09.
  8. 1 2 Cahn P, Cassetti I, Wood R, Phanuphak P, Shiveley L, Bethell RC, Sawyer J (June 2006). "Efficacy and tolerability of 10-day monotherapy with apricitabine in antiretroviral-naive, HIV-infected patients". AIDS. 20 (9): 1261–1268. doi: 10.1097/01.aids.0000232233.41877.63 . PMID   16816554. S2CID   19607533.
  9. ↑ Cox S, Moore S, Southby J, Alsumde A (August 5, 2008). Safety profile of apricitabine, a novel NRTI, during 24-week dosing in experienced HIV-1 infected patients. XVII International AIDS Conference (AIDS 2008). Mexico City. Abstract TUAB0106. Archived from the original on July 24, 2011. Retrieved 2008-08-29. Lay summary
  10. ↑ Oliveira M, Moisi D, Spira B, Cox S, Brenner BG, Wainberg MA (April 2009). "Apricitabine does not select additional drug resistance mutations in tissue culture in human immunodeficiency virus type 1 variants containing K65R, M184V, or M184V plus thymidine analogue mutations". Antimicrobial Agents and Chemotherapy. 53 (4): 1683–1685. doi:10.1128/AAC.01168-08. PMC   2663123 . PMID   19223637.
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