Dolutegravir

Dolutegravir (DTG), sold under the brand name Tivicay, is an antiretroviral medication used, together with other medication, to treat HIV/AIDS.[4] It may also be used, as part of post exposure prophylaxis, to prevent HIV infection following potential exposure.[5] It is taken by mouth.[4]

Dolutegravir

Clinical data
Trade names	Tivicay, Tivicay PD
Other names	GSK572, S-349572
AHFS/Drugs.com	Monograph
MedlinePlus	a613043
License data	EU EMA: by INN US DailyMed: Dolutegravir US FDA: Dolutegravir
Pregnancy category	AU: B1[1]
Routes of administration	By mouth
ATC code	J05AJ03 (WHO) J05AR13 (WHO) J05AR21 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) UK: POM (Prescription only) US: ℞-only [2] EU: Rx-only [3] In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	n/a[2]
Protein binding	≥98.9%
Metabolism	UGT1A1 and CYP3A
Elimination half-life	~14 hours
Excretion	Feces (53%) and urine (18.9%)
Identifiers
IUPAC name (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	1051375-16-6
PubChem CID	54726191
IUPHAR/BPS	7365
DrugBank	DB08930
ChemSpider	25051637
UNII	DKO1W9H7M1
KEGG	D10066
ChEBI	CHEBI:76010
ChEMBL	ChEMBL1229211
PDB ligand	DLU (PDBe, RCSB PDB)
CompTox Dashboard (EPA)	DTXSID90909356
ECHA InfoCard	100.237.735
Chemical and physical data
Formula	C20H19F2N3O5
Molar mass	419.385 g·mol^−1
3D model (JSmol)	Interactive image
SMILES C[C@@H]1CCO[C@@H]2N1C(=O)c3c(c(=O)c(cn3C2)C(=O)NCc4ccc(cc4F)F)O
InChI 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 Key:RHWKPHLQXYSBKR-BMIGLBTASA-N
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Common side effects include trouble sleeping, feeling tired, diarrhea, high blood sugar, and headache.[5] Severe side effects may include allergic reactions and liver problems.[5] There is tentative concerns that use during pregnancy can result in harm to the baby.[5] It is unclear if use during breastfeeding is safe.[5] Dolutegravir is an HIV integrase strand transfer inhibitor which blocks the functioning of HIV integrase which is needed for viral replication.[5]

Dolutegravir was approved for medical use in the United States in 2013.[5] It is on the World Health Organization's List of Essential Medicines.[6] Abacavir/dolutegravir/lamivudine, a combination with abacavir and lamivudine is also available.[5] As of 2019, the World Health Organization (WHO) recommends DTG as the first- and second-line treatment for all persons with HIV.[7]

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.[8]

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.[3]

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).[9]

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.[10] 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.[2]

Pregnancy

There is tentative concerns that use during pregnancy can result in harm to the baby.[5] Effective birth control is thus recommended while on dolutegravir, with pregnancy testing before starting treatment.[11] Use during the first trimester should only occur if there is no alternative.[11]

History

In February 2013, the U.S. Food and Drug Administration (FDA) announced that it would fast track dolutegravir's approval process.[12] On August 13, 2013, dolutegravir was approved for medical use in the United States.[13] On November 4, 2013, dolutegravir was approved by Health Canada.[14] On January 16, 2014, it was approved by the European Commission for use throughout the European Union.[3]

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.

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.[9] 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.[9][15]

The U.S. Food and Drug Administration (FDA) granted the approval of Tivicay and Tivicay PD to ViiV Healthcare.[9]

References

1. "Dolutegravir (Tivicay) Use During Pregnancy". Drugs.com. 16 October 2018. Retrieved 13 February 2020.
2. "Tivicay- dolutegravir sodium tablet, film coated". DailyMed. 24 October 2019. Retrieved 13 February 2020.
3. "Tivicay EPAR". European Medicines Agency (EMA). Retrieved 13 February 2020.
4. British national formulary : BNF 69 (69 ed.). British Medical Association. 2015. p. 429. ISBN 9780857111562.
5. "Dolutegravir Sodium Monograph for Professionals". Drugs.com. Retrieved 20 April 2019.
6. 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.
7. "WHO recommends dolutegravir as preferred HIV treatment option in all populations". World Health Organization (Press release). Retrieved 2019-07-22.
8. FDA approves new drug to treat HIV infection https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm364744.htm August 12, 2013
9. "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.
10. "U.S. FDA approves GlaxoSmithKline's HIV drug Tivicay". Reuters. 12 August 2013. Retrieved 13 February 2020.
11. "Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 1-4 October 2018". European Medicines Agency (EMA). 5 October 2018.
12. "GSK wins priority status for new HIV drug in U.S". Reuters. 16 February 2013. Retrieved 18 February 2013.
13. "Drug Approval Package: Tivicay (dolutegravir) Tablets NDA #204790". U.S. Food and Drug Administration (FDA). 13 September 2013. Retrieved 12 June 2020.
14. "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.
15. "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.

External links

• "Dolutegravir". Drug Information Portal. U.S. National Library of Medicine.