Atazanavir

Atazanavir, sold under the brand name Reyataz among others, is an antiretroviral medication used to treat HIV/AIDS.[2] It is generally recommended for use with other antiretrovirals.[2] It may be used for prevention after a needlestick injury or other potential exposure (postexposure prophylaxis (PEP)).[2] It is taken by mouth once a day.[2]

Atazanavir
Clinical data
Pronunciation/ˌætəˈzænəvɪər/ AT-ə-ZAN-ə-veer[1]
Trade namesReyataz, Evotaz, others[2]
AHFS/Drugs.comMonograph
MedlinePlusa603019
License data
Pregnancy
category
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability60-68%
Protein binding86%
MetabolismLiver (CYP3A4-mediated)
Elimination half-life6.5 hours
ExcretionFecal and kidney
Identifiers
IUPAC name
  • methyl N-[(1S)-1-{[(2S,3S)-3-hydroxy-4-[(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethyl-N'-{[4-(pyridin-2-yl)phenyl]methyl}butanehydrazido]-1-phenylbutan-2-yl]carbamoyl}-2,2-dimethylpropyl]carbamate
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
NIAID ChemDB
CompTox Dashboard (EPA)
ECHA InfoCard100.243.594
Chemical and physical data
FormulaC38H52N6O7
Molar mass704.869 g·mol−1
3D model (JSmol)
SMILES
  • O=C(OC)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)Cc3ccc(c2ncccc2)cc3)C(C)(C)C
InChI
  • InChI=1S/C38H52N6O7/c1-37(2,3)31(41-35(48)50-7)33(46)40-29(22-25-14-10-9-11-15-25)30(45)24-44(43-34(47)32(38(4,5)6)42-36(49)51-8)23-26-17-19-27(20-18-26)28-16-12-13-21-39-28/h9-21,29-32,45H,22-24H2,1-8H3,(H,40,46)(H,41,48)(H,42,49)(H,43,47)/t29-,30-,31+,32+/m0/s1 Y
  • Key:AXRYRYVKAWYZBR-GASGPIRDSA-N Y
 NY (what is this?)  (verify)

Common side effects include headache, nausea, yellowish skin, abdominal pain, trouble sleeping, and fever.[2] Severe side effects include rashes such as erythema multiforme and high blood sugar.[2] Atazanavir appears to be safe to use during pregnancy.[2] It is of the protease inhibitor (PI) class and works by blocking HIV protease.[2]

Atazanavir was approved for medical use in the United States in 2003.[2] It is on the World Health Organization's List of Essential Medicines.[4] As of 2017 there is a generic version available in the United States manufactured by Teva Pharmaceuticals[5]

Medical uses
Two Reyataz 200 mg capsules

Atazanavir is used in the treatment of HIV. The efficacy of atazanavir has been assessed in a number of well-designed trials in ART-naive and ART-experienced adults.[6]

Atazanavir is distinguished from other protease inhibitors in that it has lesser effects on lipid profile and appears to be less likely to cause lipodystrophy. There may be some cross-resistant with other protease inhibitors.[2] When boosted with ritonavir it is equivalent in potency to lopinavir for use in salvage therapy in people with a degree of drug resistance, although boosting with ritonavir reduces the metabolic advantages of atazanavir.

Pregnancy

No evidence of harm has been found among pregnant women taking atazanavir. It is one of the preferred HIV medications to use in pregnant women who have not taken an HIV medication before.[7] It was not associated with any birth defects among over 2,500 live births observed. Atazanavir resulted in a better cholesterol profile and confirmed that it is a safe option during pregnancy.[7]

Contraindications

Atazanavir is contraindicated in those with previous hypersensitivity (e.g., Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions). Additionally, atazanavir should not be given with alfuzosin, rifampin, irinotecan, lurasidone, pimozide, triazolam, orally administered midazolam, ergot derivatives, cisapride, St. John's wort, lovastatin, simvastatin, sildenafil, indinavir, or nevirapine.[8]

Adverse effects

Common side effects include: nausea, jaundice, rash, headache, abdominal pain, vomiting, insomnia, peripheral neurologic symptoms, dizziness, muscle pain, diarrhea, depression and fever.[8] Bilirubin levels in the blood are normally asymptomatically raised with atazanavir, but can sometimes lead to jaundice.

Mechanism of action

Atazanavir binds to the active site HIV protease and prevents it from cleaving the pro-form of viral proteins into the working machinery of the virus.[9] If the HIV protease enzyme does not work, the virus is not infectious, and no mature virions are made.[10][11] The azapeptide drug was designed as an analog of the peptide chain substrate that HIV protease would cleave normally into active viral proteins. More specifically, atazanavir is a structural analog of the transition state during which the bond between a phenylalanine and proline is broken.[12][13] Humans do not have any enzymes that break bonds between phenylalanine and proline, so this drug will not target human enzymes.

Formulations

Atazanavir is available as a 150 mg capsule, 200 mg capsule, 300 mg capsule, and 50 mg oral powder packet.[8] The 300 mg capsule should reduce pill burden, as one 300 mg capsule may replace two 150 mg capsules. Nanoformulation of atazanavir is being tested in primates together with PI-booster ritonavir and NtRTI tenofovir for a long-acting therapy.[14]

References
  1. "Atazanavir". MedlinePlus. National Institutes of Health. October 15, 2012. Archived from the original on August 2, 2013. Retrieved August 3, 2013.
  2. "Atazanavir Sulfate". The American Society of Health-System Pharmacists. Archived from the original on 20 December 2016. Retrieved 28 November 2016.
  3. "Atazanavir (Reyataz) Use During Pregnancy". Drugs.com. 27 February 2020. Retrieved 15 September 2020.
  4. World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  5. "Teva Announces Exclusive Launch of a Generic Version of Reyataz® in the United States". www.businesswire.com. 2017-12-27. Retrieved 2021-09-29.
  6. Croom, KF; Dhillon, S; Keam, SJ (2009). "Atazanavir: A Review of its Use in the Management of HIV-1 Infection". Drugs. 69 (8): 1107–1140. doi:10.2165/00003495-200969080-00009. PMID 19496633.
  7. "What's New in the Guidelines? | Adult and Adolescent ARV Guidelines". AIDSinfo. Archived from the original on 2016-11-15. Retrieved 2016-11-10.
  8. "Reyataz Package Insert" (PDF). Drugs@FDA. Food and Drug Administration. September 2016. Archived (PDF) from the original on November 11, 2016. Retrieved November 10, 2016.
  9. "Atazanavir". DrugBank. 9 November 2016. Archived from the original on 9 November 2016.
  10. Kohl, NE; Emini, EA; Schleif, WA; Davis, LJ; Heimbach, JC; Dixon, RA; Scolnick, EM; Sigal, IS (1 July 1988). "Active human immunodeficiency virus protease is required for viral infectivity". Proceedings of the National Academy of Sciences of the United States of America. 85 (13): 4686–4690. Bibcode:1988PNAS...85.4686K. doi:10.1073/pnas.85.13.4686. ISSN 0027-8424. PMC 280500. PMID 3290901.
  11. Lv, Z; Chu, Y; Wang, Y (2015). "HIV protease inhibitors: a review of molecular selectivity and toxicity". HIV/AIDS: Research and Palliative Care. 7: 95–104. doi:10.2147/HIV.S79956. PMC 4396582. PMID 25897264.
  12. Graziani, Amy L (June 17, 2014). "HIV protease inhibitors". UpToDate.
  13. Bold, G; Fässler, A; Capraro, HG; Cozens, R; Klimkait, T; Lazdins, J; Mestan, J; Poncioni, B; Rösel, J; Stover, D; Tintelnot-Blomley, M; Acemoglu, F; Beck, W; Boss, E; Eschbach, M; Hürlimann, T; Masso, E; Roussel, S; Ucci-Stoll, K; Wyss, D; Lang, M (August 1998). "New Aza-Dipeptide Analogues as Potent and Orally Absorbed HIV-1 Protease Inhibitors: Candidates for Clinical Development". Journal of Medicinal Chemistry. 41 (18): 3387–3401. doi:10.1021/jm970873c. PMID 9719591.
  14. Perazzolo S, Shireman LM, McConnachie LA, Koehn J, Shen DD, Ho RJ (Dec 2018). "Three HIV drugs, atazanavir, ritonavir, and tenofovir, co-formulated in drug-combination nanoparticles exhibit long-acting and lymphocyte-targeting properties in nonhuman primates". Journal of Pharmaceutical Sciences. 107 (12): 3153–3162. doi:10.1016/j.xphs.2018.07.032. PMC 6553477. PMID 30121315.
  • "Atazanavir". Drug Information Portal. U.S. National Library of Medicine.
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