Dolutegravir
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| Clinical data |
| Trade names |
Tivicay |
| AHFS/Drugs.com |
Monograph |
| MedlinePlus |
a613043 |
| License data |
- EU EMA: by INN
- US FDA: Dolutegravir
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Pregnancy
category |
- US: B (No risk in non-human studies)
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Routes of
administration |
By mouth |
| ATC code |
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| Legal status |
| Legal status |
- UK: POM (Prescription only)
- US: ℞-only
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| Pharmacokinetic data |
| Bioavailability |
n/a[1] |
| Protein binding |
≥98.9% |
| Metabolism |
UGT1A1 and CYP3A |
| Biological 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
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| CAS Number |
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| PubChem CID |
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| IUPHAR/BPS |
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| ChemSpider |
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| UNII |
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| KEGG |
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| ChEMBL |
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| NIAID ChemDB |
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| Chemical and physical data |
| Formula |
C20H19F2N3O5 |
| Molar mass |
419.38 g/mol |
| 3D model (JSmol) |
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SMILES
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C[C@@H]1CCO[C@@H]2N1C(=O)c3c(c(=O)c(cn3C2)C(=O)NCc4ccc(cc4F)F)O
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InChI
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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 Y
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Key:RHWKPHLQXYSBKR-BMIGLBTASA-N Y
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| NY (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.[2] It may also be used, as part of post exposure prophylaxis, to prevent HIV infection following potential exposure.[3] It is taken by mouth.[2]
Common side effects include trouble sleeping, feeling tired, diarrhea, high blood sugar, and headache.[3] Severe side effects may include allergic reactions and liver problems.[3] It is unclear if use during pregnancy or breastfeeding is safe.[3] Dolutegravir is an HIV integrase strand transfer inhibitor which blocks the functioning of HIV integrase which is needed for viral replication.[3]
Dolutegravir was approved for medical use in the United States in 2013.[3] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[4] In 2015, the cost of the medication in the United Kingdom was £499 per month.[2] Abacavir/dolutegravir/lamivudine, a combination with abacavir and lamivudine is also available.[3]
Contents
- 1 Medical use
- 2 Adverse effects
- 3 History
- 4 Clinical trials
- 5 References
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.[5]
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.[6] 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.[1]
History
In February, 2013 the Food and Drug Administration announced that it would fast track dolutegravir's approval process.[7] On August 13, 2013, dolutegravir was approved by the FDA. On November 4, 2013, dolutegravir was approved by Health Canada.[8] On January 16, 2014, it was approved by the European Commission for use throughout the European Union.[9]
Clinical trials
Dolutegravir has been compared against both other integrase nuclear strand inhibitors as well as other classes of HIV anti-retrovirals.
SPRING-2 compared dolutegravir to another integrase inhibitor, raltegravir. Both were coformulated with a choice of TDF/FTC or ABC/3TC as a backbone. After 48 weeks of treatment 88% of those on dolutegravir had less than 50 copies of HIV per mL compared to 85% in the raltegravir group, thus demonstrating non-inferiority.[10]
The FLAMINGO study was an open-label trial of dolutegravir versus darunavir boosted with ritonavir. In this trial 90% of those on dolutegravir based regimens had viral loads < 50 at 48 weeks compared to 83% in the darunavir/r. This 7% difference was statistically significant for superiority of the dolutegravir based regimens.[11]
Another trial comparing dolutegravir to efavirenz, SINGLE, was the first trial to show statistical superiority to an efavirenz/FTC/TDF coformulated regimen for treatment naive patients.[12] After 48 weeks of treatment, 88% of the dolutegravir group had HIV RNA levels < 50 copies / mL versus 81% of the efavirenz group. This has led one commentator to predict that it may replace efavirenz as the first line choice for initial therapy as it can also be formulated in one pill, once-a-day regimens.[13]
Dolutegravir has also been studied in patients who have been on previous antiretroviral medications. The VIKING trial looked at patients who had known resistance to the first generation integrase inhibitor raltegravir. After 24 weeks 41% of patients on 50 mg dolutegravir once daily and 75% of patients on 50 mg twice daily (both along with an optimized background regimen) achieved an HIV RNA viral load of < 50 copies per mL. This demonstrated that there was little clinical cross-resistance between the two integrase inhibitors.[14]
References
- ^ a b "Tivicay® (dolutegravir) Tablets for Oral Use. Full Prescribing Information" (PDF). ViiV Healthcare, 2013. Archived from the original (PDF) on 3 January 2014. Retrieved 9 February 2014.
- ^ a b c British national formulary : BNF 69 (69 ed.). British Medical Association. 2015. p. 429. ISBN 9780857111562.
- ^ a b c d e f g "Dolutegravir Sodium". The American Society of Health-System Pharmacists. Retrieved 8 December 2017.
- ^ "WHO Model List of Essential Medicines (20th List)" (PDF). World Health Organization. March 2017. Retrieved 29 June 2017.
- ^ FDA approves new drug to treat HIV infection http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm364744.htm Aug. 12, 2013
- ^ U.S. FDA approves GlaxoSmithKline's HIV drug Tivicay https://www.reuters.com/article/2013/08/12/us-glaxosmithkline-hivdrug-idUSBRE97B0WU20130812 Mon Aug 12, 2013 6:40pm EDT
- ^ "GSK wins priority status for new HIV drug in U.S". Reuters. 16 February 2013. Retrieved 18 February 2013.
- ^ "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.
- ^ EMA Tivicay information page: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002753/human_med_001720.jsp&mid=WC0b01ac058001d124
- ^ Raffi, F; Jaeger, H; Quiros-Roldan, E; Albrecht, H; Belonosova, E; Gatell, JM; Baril, JG; Domingo, P; Brennan, C; Almond, S; Min, S; extended SPRING-2 Study Group (Nov 2013). "Once-daily dolutegravir versus twice-daily raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96 week results from a randomised, double-blind, non-inferiority trial". The Lancet Infectious Diseases. 13 (11): 927–35. doi:10.1016/s1473-3099(13)70257-3. PMID 24074642.
- ^ Clotet, B; Feinberg, J; van Lunzen, J; Khuong-Josses, MA; Antinori, A; Dumitru, I; Pokrovskiy, V; Fehr, J; Ortiz, R; Saag, M; Harris, J; Brennan, C; Fujiwara, T; Min, S (June 2014). "Once-daily dolutegravir versus darunavir plus ritonavir in antiretroviral-naive adults with HIV-1 infection (FLAMINGO): 48 week results from the randomised open-label phase 3b study". The Lancet. 383: 2222–2231. doi:10.1016/S0140-6736(14)60084-2. PMID 24698485.
- ^ Walmsley, Sharon L.; Antela, Antonio; Clumeck, Nathan; Duiculescu, Dan; Eberhard, Andrea; Gutiérrez, Felix; Hocqueloux, Laurent; Maggiolo, Franco; Sandkovsky, Uriel; Granier, Catherine; Pappa, Keith; Wynne, Brian; Min, Sherene; Nichols, Garrett (7 November 2013). "Dolutegravir plus Abacavir–Lamivudine for the Treatment of HIV-1 Infection". New England Journal of Medicine. 369 (19): 1807–1818. doi:10.1056/NEJMoa1215541.
- ^ Sax, Paul. "SINGLE Study Underscores Waning of the Efavirenz Era — But Probably Just in the USA". Retrieved 19 December 2013.
- ^ Eron, JJ; Clotet, B; Durant, J; Katlama, C; Kumar, P; Lazzarin, A; Poizot-Martin, I; Richmond, G; Soriano, V; Ait-Khaled, M; Fujiwara, T; Huang, J; Min, S; Vavro, C; Yeo, J; VIKING Study Group (Mar 1, 2013). "Safety and efficacy of dolutegravir in treatment-experienced subjects with raltegravir-resistant HIV type 1 infection: 24-week results of the VIKING Study". The Journal of Infectious Diseases. 207 (5): 740–8. doi:10.1093/infdis/jis750. PMC 3563307 . PMID 23225901.
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Antiviral drugs: antiretroviral drugs used against HIV (primarily J05)
|
Entry/fusion inhibitors
(Discovery and development) |
- gp41 (Enfuvirtide (ENF, T-20))
- CCR5 (Maraviroc (MVC)
- Vicriviroc†, Cenicriviroc†, PRO 140†)
- CD4 (Ibalizumab†)
- gp120 (Fostemsavir†)
|
Reverse-transcriptase
inhibitors (RTIs) |
Nucleoside and
nucleotide (NRTI) |
- Nucleoside analogues/NRTIs: Abacavir (ABC)°#
- Didanosine (ddI)
- Emtricitabine (FTC)°
- Lamivudine (3TC)°#
- Stavudine (d4T)#
- Zidovudine (AZT, ZDV)#
- Amdoxovir†
- Apricitabine†
- Censavudine†
- Elvucitabine†
- Racivir†
- Stampidine†
- 4′-Ethynyl-2-fluoro-2′-deoxyadenosine(EFdA)§
- Zalcitabine (ddC)◊
- Nucleotide analogues/NtRTIs: Tenofovir disoproxil (TDF)°#
- Tenofovir alafenamide (TAF)
|
Non-nucleoside (NNRTI)
(Discovery and development) |
| 1st generation |
- Efavirenz (EFV)°#
- Nevirapine (NVP)#
- Delavirdine (DLV)◊
|
| 2nd generation |
- diarylpyrimidines
- Etravirine (ETR)
- Rilpivirine (RPV)°
- Doravirine†
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|
|
Integrase inhibitors
(Integrase strand transfer inhibitors (INSTI)) |
- Dolutegravir (DTG)°
- Elvitegravir (EVG)°
- Raltegravir (RAL)°
- BI 224436†
- Globoidnan A (experimental)
- Cabotegravir†
- Bictegravir (BIC)†
- MK-2048†
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| Maturation inhibitors |
|
Protease Inhibitors (PI)
(Discovery and development) |
| 1st generation |
- Amprenavir (APV)◊
- Fosamprenavir (FPV)
- Indinavir (IDV)◊
- Lopinavir (LPV)
- Nelfinavir (NFV)
- Ritonavir (RTV)#
- Saquinavir (SQV)#
|
| 2nd generation |
- Atazanavir (ATV)°#
- Darunavir (DRV)°#
- Tipranavir (TPV)
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| Combined formulations |
- Abacavir/lamivudine°#
- Abacavir/dolutegravir/lamivudine°
- Abacavir/lamivudine/zidovudine
- Atazanavir/cobicistat
- Bictegravir/emtricitabine/tenofovir alafenamide
- Darunavir/cobicistat
- Efavirenz/emtricitabine/tenofovir°#
- Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide
- Elvitegravir/cobicistat/emtricitabine/tenofovir°
- Emtricitabine/tenofovir alafenamide
- Emtricitabine/rilpivirine/tenofovir alafenamide
- Emtricitabine/rilpivirine/tenofovir°
- Emtricitabine/tenofovir°#
- Lamivudine/raltegravir
- Lamivudine/zidovudine#
- Lopinavir/ritonavir°#
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| Pharmacokinetic boosters |
- Cobicistat (c)
- Ritonavir (r)#
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| Experimental agents |
| Uncoating inhibitors |
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| Transcription inhibitors |
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| Translation inhibitors |
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| Other |
- Abzyme
- BIT225†
- Calanolide A
- Ceragenin
- Cyanovirin-N
- Diarylpyrimidines
- Epigallocatechin gallate (EGCG)
- KP-1461†
- Foscarnet
- Fosdevirine†
- Griffithsin
- Hydroxycarbamide
- Miltefosine
- Portmanteau inhibitors
- Scytovirin
- Seliciclib†
- Synergistic enhancers
- Tre recombinase
- Zinc finger protein transcription factor
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| Failed agents |
- Aplaviroc
- Atevirdine
- Brecanavir
- Capravirine
- Dexelvucitabine
- Droxinavir
- Lasinavir
- Emivirine
- Lersivirine
- Lodenosine
- Loviride
- Mozenavir
- Palinavir
- Telinavir
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- #WHO-EM
- ‡Withdrawn from market
- Clinical trials:
- †Phase III
- §Never to phase III
°DHHS recommended initial regimen options. ◊Formerly or rarely used agent.
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