Chemistry:Bictegravir

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Bictegravir (INN; BIC, formerly known as GS-9883)[1][2] 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.[3][4] 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.[5]

The combination drug bictegravir/emtricitabine/tenofovir alafenamide (Biktarvy) was approved for use in 2018 in Australia,[6] the European Union[7] and the United States[8] and in 2019 in New Zealand[9] and the United Kingdom;[10] a generic version was approved by the Drugs Controller General of India in 2019.[11] As of 2024, it is recommended as a first-line choice of antiretroviral therapy in several countries, including the European Union,[12] the United Kingdom[13] and the United States.[14]

Medical use

Bictegravir is used in a fixed-dose combination with tenofovir alafenamide and emtricitabine for the treatment of HIV-1 infection.[4][15]

Contraindication

Bictegravir should not be used with dofetilide and rifampin.[16] Use of dofetilide with bictegravir increases the concentration of dofetilide, which can lead to life-threatening events.[16] Concomitant use of bictegravir and rifampin causes significant interactions because of an effect rifampin has on bictegravir.[16] Bictagravir is metabolized primarily through the liver (CYP3A4), so inducers of CYP3A4 should be avoided.[4]

Adverse effects

The most common side effects seen in bictegravir use include diarrhea, nausea, and headache.[4]

Society and culture

Economics

In February 2022, Gilead agreed to pay ViiV Healthcare over $1 billion to settle patent infringement cases.[17][18]

Synthesis

A couple of syntheses of bictegravir were recently reported.[19][20] Below is one of them:

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The condensation of Meldrum's acid [2033-24-1] (1) with methoxyacetic acid [625-45-6] (2) in the presence of pivaloyl chloride gave rise to [343246-51-5] (3). Treatment of this intermediate with 2,4,6-trifluorobenzylamine [214759-21-4] (4) and TFA gave β-ketoamide, 4-methoxy-3-oxo-N-(2,4,6-trifluorobenzyl)butanamide [1846582-16-8] (5). The reaction with DMF-DMA followed by condensation with 2,2-Dimethoxyethylamine [22483-09-6] (6) yielded vinylogous amide, PC154010209 (7). Next, a cyclization reaction occurred upon treatment with dimethyl oxalate; [553-90-2 ] (8) and sodium methoxide giving rise to pyridone [1644158-10-0] (9) Acetal deprotection was followed by treatment with syn-aminopentanol, (1R,3S)-3-Aminocyclopentanol [1110772-05-8][124555-42-6] (10) under weakly basic conditions. This is an annulation reaction arriving at [1616340-94-3] (11). Magnesium bromide mediated demethylation completed the synthesis of bictegravir (12).

References

  1. ↑ "Recommended INN: List 75". WHO Drug Information 30 (1): 102. 2016. https://www.who.int/medicines/publications/druginformation/innlists/RL75.pdf?ua=1. Retrieved 4 October 2020. 
  2. ↑ "Bictegravir - Gilead Sciences" (in en). Adis Insight. Springer Nature Switzerland AG. http://adisinsight.springer.com/drugs/800041516. 
  3. ↑ "New integrase inhibitor bictegravir looks promising in early studies". NAM aidsmap. 6 July 2016. http://www.aidsmap.com/New-integrase-inhibitor-bictegravir-looks-promising-in-early-studies/page/3069166/. 
  4. ↑ 4.0 4.1 4.2 4.3 "Bictegravir, a novel integrase inhibitor for the treatment of HIV infection". Drugs of Today 55 (11): 669–682. November 2019. doi:10.1358/dot.2019.55.11.3068796. PMID 31840682. https://doi.org/10.1358/dot.2019.55.11.3068796. Retrieved 28 August 2023. 
  5. ↑ "Gilead Presents Preliminary Data on Bictegravir, an Investigational Integrase Strand Transfer Inhibitor for the Treatment of HIV" (Press release). Gilead Sciences. 20 June 2016. Archived from the original on 2 February 2017. Retrieved 20 January 2017.
  6. ↑ "Australian Public Assessment Report for Bictegravir / Emtricitabine / Tenofovir alafenamide". Therapeutic Goods Administration. 1 August 2019. https://www.tga.gov.au/sites/default/files/auspar-bictegravir-emtricitabine-tenofovir-alafenamide-190801.pdf. 
  7. ↑ "Biktarvy". European Medicines Agency. 21 June 2018. https://www.ema.europa.eu/en/medicines/human/EPAR/biktarvy#ema-inpage-item-authorisation-details. 
  8. ↑ "U.S. Food and Drug Administration Approves Gilead's Biktarvy (Bictegravir, Emtricitabine, Tenofovir Alafenamide) for Treatment of HIV-1 Infection" (Press release). Gilead Sciences. 7 February 2018.
  9. ↑ "BIKTARVY Data Sheet v 8.0". Medsafe. 24 August 2023. https://www.medsafe.govt.nz/profs/datasheet/b/Biktarvytab.pdf. 
  10. ↑ "Bictegravir-emtricitabine-tenofovir alafenamide for the treatment of HIV-1 in adults". NHS England. 17 July 2019. https://www.england.nhs.uk/commissioning/publication/bictegravir-emtricitabine-tenofovir-alafenamide-for-the-treatment-of-hiv-1-in-adults/. 
  11. ↑ "Hetero launches TAFFIC, the latest 3-in-1 single pill for HIV treatment" (Press release). Hetero Drugs. 17 December 2019. Retrieved 22 February 2024.
  12. ↑ "Initial Regimens: ART-naïve Adults". European AIDS Clinical Society. October 2023. https://eacs.sanfordguide.com/art/eacs-initial-regimens-arv-naive-adults. 
  13. ↑ "BHIVA guidelines on antiretroviral treatment for adults living with HIV-1 2022 (2023 interim update)". British HIV Association. 28 May 2023. p. 16. https://www.bhiva.org/file/63513a1745ea9/BHIVA-guidelines-on-antiretroviral-treatment-for-adults-living-with-HIV-1-2022.pdf. 
  14. ↑ "Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV". HIV.gov. 21 September 2022. p. 6. https://clinicalinfo.hiv.gov/sites/default/files/guidelines/documents/adult-adolescent-arv/recommendations-adult-adolescent-arv.pdf. 
  15. ↑ "Bictegravir combined with emtricitabine and tenofovir alafenamide versus dolutegravir, abacavir, and lamivudine for initial treatment of HIV-1 infection: week 96 results from a randomised, double-blind, multicentre, phase 3, non-inferiority trial". The Lancet. HIV 6 (6): e355–e363. June 2019. doi:10.1016/S2352-3018(19)30077-3. PMID 31068270. 
  16. ↑ 16.0 16.1 16.2 "Biktarvy - FDA Prescribing Highlights". https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210251s000lbl.pdf. 
  17. ↑ "GSK announces settlement between ViiV Healthcare and Gilead Sciences, Inc. resolving litigation relating to Biktarvy and ViiV's dolutegravir patents and entry into a patent licence agreement". ViiV Healthcare (Press release). ViiV Healthcare. Retrieved 26 August 2023.
  18. ↑ "GSK announces settlement between ViiV Healthcare and Gilead Sciences, Inc. resolving litigation relating to Biktarvy and ViiV's dolutegravir patents and entry into a patent licence agreement". GSK US (Press release). 1 February 2022. Retrieved 28 August 2023.
  19. ↑ "Review of Synthetic Routes and Final Forms of Integrase Inhibitors Dolutegravir, Cabotegravir, and Bictegravir". Organic Process Research & Development 23 (5): 716–729. 17 May 2019. doi:10.1021/acs.oprd.9b00031. https://pubs.acs.org/doi/10.1021/acs.oprd.9b00031. 
  20. ↑ "Synthetic Approaches to New Drugs Approved during 2018". Journal of Medicinal Chemistry 63 (19): 10652–10704. 8 October 2020. doi:10.1021/acs.jmedchem.0c00345. https://pubs.acs.org/doi/10.1021/acs.jmedchem.0c00345. 

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