Cobicistat

Cobicistat
Names
Trade namesTybost
Other namesGS-9350
IUPAC name
  • 1,3-thiazol-5-ylmethyl [(2R,5R)-5-{[(2S)-2-[(methyl{[2-(propan-2-yl)-1,3-thiazol-4-yl]methyl}carbamoyl)amino]-4-(morpholin-4-yl)butanoyl]amino}-1,6-diphenylhexan-2-yl]carbamate
Clinical data
Drug classCYP3A inhibitor[1]
Main usesHIV/AIDS[1]
Side effectsJaundice, nausea, rash[1][2]
InteractionsMany[2]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Typical dose150 mg OD[1]
External links
AHFS/Drugs.comMonograph
MedlinePlusa616029
Legal
License data
Legal status
Chemical and physical data
FormulaC40H53N7O5S2
Molar mass776.03 g·mol−1
3D model (JSmol)
SMILES
  • CC(C)c1nc(cs1)CN(C)C(=O)NC(CCN2CCOCC2)C(=O)NC(CCC(Cc3ccccc3)NC(=O)OCc4cncs4)Cc5ccccc5
InChI
  • InChI=1S/C40H53N7O5S2/c1-29(2)38-43-34(27-53-38)25-46(3)39(49)45-36(16-17-47-18-20-51-21-19-47)37(48)42-32(22-30-10-6-4-7-11-30)14-15-33(23-31-12-8-5-9-13-31)44-40(50)52-26-35-24-41-28-54-35/h4-13,24,27-29,32-33,36H,14-23,25-26H2,1-3H3,(H,42,48)(H,44,50)(H,45,49)/t32-,33-,36+/m1/s1 checkY
  • Key:ZCIGNRJZKPOIKD-CQXVEOKZSA-N checkY

Cobicistat, sold under the brand name Tybost, is a medication used to treat HIV/AIDS.[1] It is often used to boost the effects of atazanavir or darunavir.[1] It is taken by mouth.[1] Additionally it is available as part of a number of combination medications.[3]

Common side effects include jaundice, nausea, and rash.[1][2] Use is not recommended in pregnancy.[2] Use is not recommended in those with severe liver problems.[3] It has a number of important medication interactions.[2] It works by blocking the action of a group of liver enzymes called CYP3A; thereby slowing the breakdown of atazanavir or darunavir.[1]

Cobicistat was approved for medical use in the United States in 2012 and Europe in 2013.[2][1] In the United Kingdom a month of medication costs the NHS about £21 as of 2021.[3] This amount in the United States costs about 270 USD.[4]

Medical uses

Dosage

It is generally taken at a dose of 150 mg once per day with food.[1] It is taken at the same time as either atazanavir 300 mg or darunavir 800 mg.[2]

Combination medications

Cobicistat is a component of three combination medications: elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil (Stribild) which was approved in the United States in 2012;[5][6] elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (Genvoya) which was approved in the United States in 2015; and cobicistat/darunavir/emtricitabine/tenofovir alafenamide (Symtuza) which was approved in the United States in 2018.[7]

Additional combinations include cobicistat and the protease inhibitor darunavir as darunavir/cobicistat (Prezcobix), and cobicistat and protease inhibitor atazanavir as atazanavir/cobicistat (Evotaz); both approved in 2015.

Mechanism of action

Cobicistat is a potent inhibitor of cytochrome P450 3A enzymes, including the important CYP3A4 subtype.[8] It also inhibits intestinal transport proteins, increasing the overall absorption of several HIV medications, including atazanavir, darunavir, and tenofovir alafenamide.[9]

Like ritonavir, it is used to inhibit liver enzymes that metabolize other HIV medications. In contrast with ritonavir, the other booster approved for use as a part of HAART, cobicistat has no anti-HIV activity of its own.[5]

Chemistry

Cobicistat is a drug analogue of ritonavir, in which the valine moiety is exchanged for a 2-morpholinoethyl group, and the backbone hydroxyl group is removed. These changes effectively eliminate the anti-HIV activity of ritonavir while preserving its inhibitory effects on the CYP3A isozyme family of proteins.[10] Cobicistat is therefore able to increase plasma concentration of other coadministered anti-HIV drugs without the risk of causing cobicistat-resistant mutations in the HIV virus.

Synthesis

Cobicistat may be synthesized from any number of commercially available starting materials. The synthesis shown below utilizes L-methionine and bromoacetic acid as starting materials.[11]

History

Cobicistat was developed through structure-activity relationship studies using ritonavir and desoxyritonavir as lead compounds. These studies were conducted by scientists at Gilead Sciences, and successfully optimized ritonavir into a potent CYP3A inhibitor lacking anti-HIV activity. Cobicistat shows potent, selective inhibition of the CYP3A isozyme family (IC50 0.15 μM) compared to some CYP1A and CYP2C isozymes.[12] As cobicistat was discovered using structure-activity relationship studies, its CYP3A binding is still poorly understood; however, research on the protein-ligand interactions between CYP3A4 and ritonavir analogues[13] demonstrates that CYP 3A4 residues Ile369, Ala370, Met371, as well as Arg105 and Ser119, play an important role in ritonavir analogue inhibition of CYP3A4.[14][15]

References

  1. 1 2 3 4 5 6 7 8 9 10 11 "Tybost". Archived from the original on 10 November 2021. Retrieved 6 January 2022.
  2. 1 2 3 4 5 6 7 "DailyMed - TYBOST- cobicistat tablet, film coated". dailymed.nlm.nih.gov. Archived from the original on 28 October 2020. Retrieved 5 January 2022.
  3. 1 2 3 BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 699. ISBN 978-0857114105.
  4. ↑ "Cobicistat Prices, Coupons & Savings Tips - GoodRx". GoodRx. Retrieved 6 January 2022.
  5. 1 2 Highleyman, L. Elvitegravir "Quad" Single-tablet Regimen Shows Continued HIV Suppression at 48 Weeks Archived 3 March 2016 at the Wayback Machine. HIV and Hepatitis.com
  6. ↑ R Elion, J Gathe, B Rashbaum, and others. The Single-Tablet Regimen of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Fumarate (EVG/COBI/FTC/TDF; Quad) Maintains a High Rate of Virologic Suppression, and Cobicistat (COBI) is an Effective Pharmacoenhancer Through 48 Weeks. 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2010). Boston, September 12–15, 2010.
  7. ↑ "Symtuza (cobicistat, darunavir, emtricitabine and tenofovir alafenamide) FDA Approval History". Drugs.com. Archived from the original on 26 May 2021. Retrieved 30 October 2019.
  8. ↑ Mathias AA, German P, Murray BP, Wei L, Jain A, West S, et al. (March 2010). "Pharmacokinetics and pharmacodynamics of GS-9350: a novel pharmacokinetic enhancer without anti-HIV activity". Clinical Pharmacology and Therapeutics. 87 (3): 322–9. doi:10.1038/clpt.2009.228. PMID 20043009. S2CID 29197109.
  9. ↑ Lepist EI, Phan TK, Roy A, Tong L, Maclennan K, Murray B, Ray AS (October 2012). "Cobicistat boosts the intestinal absorption of transport substrates, including HIV protease inhibitors and GS-7340, in vitro". Antimicrobial Agents and Chemotherapy. 56 (10): 5409–13. doi:10.1128/AAC.01089-12. PMC 3457391. PMID 22850510.
  10. ↑ Xu L, Liu H, Murray BP, Callebaut C, Lee MS, Hong A, et al. (August 2010). "Cobicistat (GS-9350): A Potent and Selective Inhibitor of Human CYP3A as a Novel Pharmacoenhancer". ACS Medicinal Chemistry Letters. 1 (5): 209–13. doi:10.1021/ml1000257. PMC 4007915. PMID 24900196.
  11. ↑ "WO 2016128885" (PDF). Archived from the original (PDF) on 14 August 2019. Retrieved 25 August 2021.
  12. ↑ Xu L, Liu H, Hong A, Vivian R, Murray BP, Callebaut C, et al. (February 2014). "Structure-activity relationships of diamine inhibitors of cytochrome P450 (CYP) 3A as novel pharmacoenhancers. Part II: P2/P3 region and discovery of cobicistat (GS-9350)". Bioorganic & Medicinal Chemistry Letters. 24 (3): 995–9. doi:10.1016/j.bmcl.2013.12.057. PMID 24412072.
  13. ↑ Sevrioukova IF, Poulos TL (July 2013). "Dissecting cytochrome P450 3A4-ligand interactions using ritonavir analogues". Biochemistry. 52 (26): 4474–81. doi:10.1021/bi4005396. PMID 23746300.
  14. ↑ Sevrioukova IF, Poulos TL (October 2010). "Structure and mechanism of the complex between cytochrome P4503A4 and ritonavir". Proceedings of the National Academy of Sciences of the United States of America. 107 (43): 18422–7. Bibcode:2010PNAS..10718422S. doi:10.1073/pnas.1010693107. PMC 2973003. PMID 20937904.
  15. ↑ "PDB 3NXU". Archived from the original on 1 September 2017. Retrieved 25 August 2021.
  • "Cobicistat". Drug Information Portal. U.S. National Library of Medicine. Archived from the original on 24 June 2021. Retrieved 25 August 2021.
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