Dolutegravir

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Dolutegravir
Dolutegravir structure.svg
Dolutegravir ball-and-stick model.png
Clinical data
Trade names Tivicay, Tivicay PD
Other namesGSK572, S-349572
AHFS/Drugs.com Monograph
MedlinePlus a613043
License data
Pregnancy
category
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability n/a [4]
Protein binding ≥98.9%
Metabolism UGT1A1 and CYP3A
Elimination half-life ~14 hours
Excretion Feces (53%) and urine (18.9%)
Identifiers
  • (4R,12aS)-N-(2,4-difluorobenzyl)-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b] [1,3]oxazine-9-carboxamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard 100.237.735 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C20H19F2N3O5
Molar mass 419.385 g·mol−1
3D model (JSmol)
  • C[C@@H]1CCO[C@@H]2N1C(=O)c3c(c(=O)c(cn3C2)C(=O)NCc4ccc(cc4F)F)O
  • InChI=1S/C20H19F2N3O5/c1-10-4-5-30-15-9-24-8-13(17(26)18(27)16(24)20(29)25(10)15)19(28)23-7-11-2-3-12(21)6-14(11)22/h2-3,6,8,10,15,27H,4-5,7,9H2,1H3,(H,23,28)/t10-,15+/m1/s1 Yes check.svgY
  • Key:RHWKPHLQXYSBKR-BMIGLBTASA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Dolutegravir (DTG), sold under the brand name Tivicay, is an antiretroviral medication used, together with other medication, to treat HIV/AIDS. [6] It may also be used, as part of post exposure prophylaxis, to prevent HIV infection following potential exposure. [7] It is taken by mouth. [6]

Contents

Common side effects include trouble sleeping, feeling tired, diarrhea, high blood sugar, and headache. [7] Severe side effects may include allergic reactions and liver problems. [7] There are tentative concerns that use during pregnancy can result in harm to the baby. [7] It is unclear if use during breastfeeding is safe. [7] Dolutegravir is an HIV integrase strand transfer inhibitor which blocks the functioning of HIV integrase which is needed for viral replication. [7]

Dolutegravir was approved for medical use in the United States in 2013. [7] It is on the World Health Organization's List of Essential Medicines. [8] Abacavir/dolutegravir/lamivudine, a combination with abacavir and lamivudine is also available. [7] [9] [10] As of 2019, the World Health Organization (WHO) recommends DTG as the first- and second-line treatment for all persons with HIV. [11]

Medical use

Dolutegravir is approved for use in a broad population of HIV-infected patients. It can be used to treat HIV-infected adults who have never taken HIV therapy (treatment-naïve) and HIV-infected adults who have previously taken HIV therapy (treatment-experienced), including those who have been treated with other integrase strand transfer inhibitors. Tivicay is also approved for children ages 12 years and older weighing at least 40 kilograms (kg) who are treatment-naïve or treatment-experienced but have not previously taken other integrase strand transfer inhibitors. [12]

In the European Union it is indicated, in combination with other anti-retroviral medicinal products, for the treatment of Human Immunodeficiency Virus (HIV) infected adults, adolescents and children above six years of age. [5]

In June 2020, the indication for dolutegravir in the US was updated to include children at least four weeks old and weighing at least 3 kg (6.61 pounds). [13]

Adverse effects

Common side effects of dolutegravir in clinical trials included insomnia and headache. Serious side effects included allergic reactions and abnormal liver function in patients who were also infected with hepatitis B or C. [14] The package insert warns against a mean rise in serum creatinine of 0.11 mg/dL due to inhibition of tubular secretion of creatinine and does not affect GFR. [4]

Pregnancy

There are tentative concerns that use during pregnancy can result in harm to the baby. [7] Effective birth control is thus recommended while on dolutegravir, with pregnancy testing before starting treatment. [15] Use during the first trimester should only occur if there is no alternative. [15]

History

In February 2013, the U.S. Food and Drug Administration (FDA) announced that it would fast track dolutegravir's approval process. [16] On 13 August 2013, dolutegravir was approved for medical use in the United States. [17] On 4 November 2013, dolutegravir was approved by Health Canada. [18] On 16 January 2014, it was approved by the European Commission for use throughout the European Union. [5]

In 2019, a triple-combination therapy, with dolutegravir replacing efavirenz, was introduced as the first-line treatment for all people (pregnant excluded) with HIV by the South African Government (public) sector.[ medical citation needed ]

In June 2020, dolutegravir was approved in the US with an indication to treat HIV-1 infection in children at least four weeks old and weighing at least 3 kg (6.61 pounds) in combination with other antiretroviral treatments. [13] It is intended to treat children at least 4 weeks old and 3 kg who have never been treated for HIV or who have been treated, but not with an integrase strand transferase inhibitor (INSTI) class drug. [13] [19]

The U.S. Food and Drug Administration (FDA) granted the approval of Tivicay and Tivicay PD to ViiV Healthcare. [13]

Related Research Articles

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">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">Abacavir</span> Chemical compound

Abacavir, sold under the brand name Ziagen among others, is a medication used to treat HIV/AIDS. Similar to other nucleoside analog reverse-transcriptase inhibitors (NRTIs), abacavir is used together with other HIV medications, and is not recommended by itself. It is taken by mouth as a tablet or solution and may be used in children over the age of three months.

<span class="mw-page-title-main">Abacavir/lamivudine/zidovudine</span> Mixture of chemical compounds

Abacavir/lamivudine/zidovudine, sold under the brand name Trizivir, is a fixed-dose combination antiretroviral medication for the treatment of HIV/AIDS. It contains three reverse transcriptase inhibitors patented by GlaxoSmithKline and marketed by a joint venture with Pfizer, ViiV Healthcare:

<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">Raltegravir</span> Chemical compound

Raltegravir, sold under the brand name Isentress, is an antiretroviral medication used, together with other medication, to treat HIV/AIDS. It may also be used, as part of post exposure prophylaxis, to prevent HIV infection following potential exposure. It is taken by mouth.

Integrase inhibitors (INIs) are a class of antiretroviral drug designed to block the action of integrase, a viral enzyme that inserts the viral genome into the DNA of the host cell. Since integration is a vital step in retroviral replication, blocking it can halt further spread of the virus. Integrase inhibitors were initially developed for the treatment of HIV infection, but have been applied to other retroviruses. The class of integrase inhibitors called integrase strand transfer inhibitors (INSTIs) are in established medical use. Other classes, such as allosteric integrase inhibitors (ALLINIs) or integrase binding inhibitors (INBIs), are still experimental.

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

Abacavir/lamivudine, sold under the brand name Kivexa among others, is a fixed-dose combination antiretroviral medication used to treat HIV/AIDS. It contains abacavir and lamivudine. It is generally recommended for use with other antiretrovirals. It is commonly used as part of the preferred treatment in children. It is taken by mouth as a tablet.

<span class="mw-page-title-main">Rilpivirine</span> HIV treatment

Rilpivirine, sold under the brand names Edurant and Rekambys, is a medication, developed by Tibotec, used for the treatment of HIV/AIDS. It is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) with higher potency, longer half-life and reduced side-effect profile compared with older NNRTIs such as efavirenz.

ViiV Healthcare is a British multinational pharmaceutical company specializing in the research and development of medicines to treat and prevent HIV/AIDS, with its global headquarters in London. The company was created as a joint venture by GSK and Pfizer in November 2009, with both companies transferring their HIV assets to the new company. In 2012, Shionogi joined the company. As of December 2023, 76.5% of the company is owned by GSK, 13.5% by Pfizer and 10% by Shionogi. According to The Financial Times, the company’s co-ownership structure may change depending on the achievement of certain milestones.

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

Tenofovir alafenamide, sold under the brand name Vemlidy, is an antiviral medication used against hepatitis B and HIV. It is used for the treatment of chronic hepatitis B virus (HBV) infection in adults with compensated liver disease and is given in combination with other medications for the prevention and treatment of HIV. It is taken by mouth.

<span class="mw-page-title-main">Cabotegravir</span> Medication for HIV/AIDS

Cabotegravir, sold under the brand name Vocabria among others, is a antiretroviral medication used for the treatment of HIV/AIDS. It is available in the form of tablets and as an intramuscular injection, as well as in an injectable combination with rilpivirine under the brand name Cabenuva.

<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.

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

Bictegravir is a second-generation integrase inhibitor (INSTI) class that was structurally derived from an earlier compound dolutegravir by scientists at Gilead Sciences. In vitro and clinical results were presented by Gilead in the summer of 2016. In 2016, bictegravir was in a Phase 3 trial as part of a single tablet regimen in combination with tenofovir alafenamide (TAF) and emtricitabine (FTC) for the treatment of HIV-1 infection.

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.

Dolutegravir/lamivudine/tenofovir (DTG/3TC/TDF) is a fixed-dose combination antiretroviral medication used to treat HIV/AIDS. It is a combination of dolutegravir, lamivudine, and tenofovir disoproxil. As of 2019, it is listed by the World Health Organization (WHO) as the first line treatment for adults, with tenofovir/lamivudine/efavirenz as an alternative. It is taken by mouth.

Dolutegravir/rilpivirine, sold under the brand name Juluca, is a fixed-dose combination antiretroviral medication for the treatment of HIV/AIDS. It contains the medicines dolutegravir and rilpivirine. It is taken by mouth.

<span class="mw-page-title-main">Cabotegravir/rilpivirine</span> Co-packaged antiretroviral medication

Cabotegravir/rilpivirine, sold under the brand name Cabenuva, is a co-packaged antiretroviral medication for the treatment of HIV/AIDS. It contains cabotegravir and rilpivirine in a package with two separate injection vials.

References

  1. ↑ "Dolutegravir (Tivicay) Use During Pregnancy". Drugs.com. 16 October 2018. Retrieved 13 February 2020.
  2. ↑ "Prescription medicines: registration of new chemical entities in Australia, 2014". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 10 April 2023.
  3. ↑ "Drug and medical device highlights 2018: Helping you maintain and improve your health". Health Canada . 14 October 2020. Retrieved 17 April 2024.
  4. 1 2 3 "Tivicay- dolutegravir sodium tablet, film coated". DailyMed. 24 October 2019. Retrieved 13 February 2020.
  5. 1 2 3 "Tivicay EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 13 February 2020.
  6. 1 2 British national formulary : BNF 69 (69 ed.). British Medical Association. 2015. p. 429. ISBN   9780857111562.
  7. 1 2 3 4 5 6 7 8 9 "Dolutegravir Sodium Monograph for Professionals". Drugs.com. Retrieved 20 April 2019.
  8. ↑ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl: 10665/325771 . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  9. ↑ Ciccullo A, Baldin G, Borghetti A, Di Giambenedetto S (April 2020). "Dolutegravir plus lamivudine for the treatment of HIV-1 infection". Expert Review of Anti-infective Therapy. 18 (4): 279–292. doi:10.1080/14787210.2020.1729742. PMID   32067525. S2CID   211160876.
  10. ↑ Patel R, Evitt L, Mariolis I, Di Giambenedetto S, d'Arminio Monforte A, Casado J, et al. (August 2021). "HIV Treatment with the Two-Drug Regimen Dolutegravir Plus Lamivudine in Real-world Clinical Practice: A Systematic Literature Review". Infectious Diseases and Therapy. 10 (4): 2051–2070. doi:10.1007/s40121-021-00522-7. PMC   8572911 . PMID   34426899.
  11. ↑ "WHO recommends dolutegravir as preferred HIV treatment option in all populations". World Health Organization (Press release). Retrieved 22 July 2019.
  12. ↑ "FDA approves new drug to treat HIV infection". Food and Drug Administration . 12 August 2013. Archived from the original on 8 February 2014.
  13. 1 2 3 4 "FDA Approves Drug to Treat Infants and Children with HIV". U.S. Food and Drug Administration (FDA) (Press release). 12 June 2020. Retrieved 12 June 2020.
  14. ↑ "U.S. FDA approves GlaxoSmithKline's HIV drug Tivicay". Reuters. 12 August 2013. Retrieved 13 February 2020.
  15. 1 2 "Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 1-4 October 2018". European Medicines Agency (EMA). 5 October 2018.
  16. ↑ "GSK wins priority status for new HIV drug in U.S". Reuters . 16 February 2013. Archived from the original on 19 February 2013. Retrieved 18 February 2013.
  17. ↑ "Drug Approval Package: Tivicay (dolutegravir) Tablets NDA #204790". U.S. Food and Drug Administration (FDA). 13 September 2013. Retrieved 12 June 2020.
  18. ↑ "ViiV Healthcare receives approval for Tivicay (dolutegravir) in Canada for the treatment of HIV" (PDF). Archived from the original (PDF) on 12 November 2013. Retrieved 11 November 2013.
  19. ↑ "ViiV Healthcare announces US FDA approval of the first-ever dispersible tablet formulation of dolutegravir, Tivicay PD, a once-daily treatment for children living with HIV". GSK (Press release). Retrieved 12 June 2020.
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