|Drug class||CYP3A inhibitor|
|Side effects||Jaundice, nausea, rash|
|Typical dose||150 mg OD|
|Chemical and physical data|
|Molar mass||776.03 g·mol−1|
|3D model (JSmol)|
|(what is this?)|
Cobicistat, sold under the brand name Tybost, is a medication used to treat HIV/AIDS. It is often used to boost the effects of atazanavir or darunavir. It is taken by mouth. Additionally it is available as part of a number of combination medications.
Common side effects include jaundice, nausea, and rash. Use is not recommended in pregnancy. Use is not recommended in those with severe liver problems. It has a number of important medication interactions. It works by blocking the action of a group of liver enzymes called CYP3A; thereby slowing the breakdown of atazanavir or darunavir.
Cobicistat was approved for medical use in the United States in 2012 and Europe in 2013. In the United Kingdom a month of medication costs the NHS about £21 as of 2021. This amount in the United States costs about 270 USD.
Cobicistat is a component of three combination medications: elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil (Stribild) which was approved in the United States in 2012; 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.
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. It also inhibits intestinal transport proteins, increasing the overall absorption of several HIV medications, including atazanavir, darunavir, and tenofovir alafenamide.
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.
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. 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.
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. 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 demonstrates that CYP 3A4 residues Ile369, Ala370, Met371, as well as Arg105 and Ser119, play an important role in ritonavir analogue inhibition of CYP3A4.
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- WO 2016128885
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- PDB 3NXU
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