Dolutegravir

Dolutegravir
Systematic (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
Clinical data
Trade names Tivicay
AHFS/Drugs.com Multum Consumer Information
MedlinePlus a613043
Licence data EMA:Link, US FDA:link
  • US: B (No risk in non-human studies)
Oral
Pharmacokinetic data
Bioavailability n/a[1]
Protein binding ≥98.9%
Metabolism UGT1A1 and CYP3A
Half-life ~14 hours
Excretion Feces (53%) and urine (18.9%)
Identifiers
1051375-16-6 
J05AX12
PubChem CID 54726191
ChemSpider 25051637 Yes
UNII DKO1W9H7M1 Yes
ChEMBL CHEMBL1229211 Yes
NIAID ChemDB 538122
Chemical data
Formula C20H19F2N3O5
419.38 g/mol
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Dolutegravir[2] (DTG) is an FDA-approved drug[3] for the treatment of HIV infection. Dolutegravir is an integrase inhibitor. Known as S/GSK1349572 or just "572" the drug is marketed as Tivicay[4] by GlaxoSmithKline (GSK). In February, 2013 the Food and Drug Administration announced that it would fast track dolutegravir's approval process.[5] On August 13, 2013, dolutegravir was approved by the FDA. On November 4, 2013, dolutegravir was approved by Health Canada.[6] On January 16, 2014, Tivicay was approved by the European Commission for use throughout the European Union.[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.[3]

Adverse effects

Common side effects of Tivicay 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.[8] 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]

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.[9]

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.[10]

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.[11] 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.[12]

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.[13]

References

  1. ↑ 1.0 1.1 "Tivicay® (dolutegravir) Tablets for Oral Use. Full Prescribing Information" (PDF). ViiV Healthcare, 2013. Retrieved 9 February 2014.
  2. ↑ "Statement on a Nonproprietary Name Adopted by the USAN Council" (PDF). American Medical Association (AMA). Retrieved 9 February 2014.
  3. ↑ 3.0 3.1 FDA approves new drug to treat HIV infection http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm364744.htm Aug. 12, 2013
  4. ↑ "U.S. FDA approves GlaxoSmithKline's HIV drug Tivicay". Reuters. 12 August 2013. Retrieved 13 February 2013.
  5. ↑ "GSK wins priority status for new HIV drug in U.S". Reuters. 16 February 2013. Retrieved 18 February 2013.
  6. ↑ "ViiV Healthcare receives approval for Tivicay™ (dolutegravir) in Canada for the treatment of HIV" (PDF). Retrieved 11 November 2013.
  7. ↑ EMA Tivicay information page: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002753/human_med_001720.jsp&mid=WC0b01ac058001d124
  8. ↑ U.S. FDA approves GlaxoSmithKline's HIV drug Tivicay http://www.reuters.com/article/2013/08/12/us-glaxosmithkline-hivdrug-idUSBRE97B0WU20130812 Mon Aug 12, 2013 6:40pm EDT
  9. ↑ 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.
  10. ↑ "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". 7/4/2014. doi:10.1016/S0140-6736(14)60084-2. Check date values in: |date= (help)
  11. ↑ 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.
  12. ↑ Sax, Paul. "SINGLE Study Underscores Waning of the Efavirenz Era — But Probably Just in the USA". Retrieved 19 December 2013.
  13. ↑ 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. PMID 23225901.