Atazanavir

Atazanavir

Systematic (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
Clinical data
Pronunciation	/ˌæ.tə.ˈzæ.nə.vɪər/, A-tə-ZA-nə-vir[1]
AHFS/Drugs.com	monograph
MedlinePlus	a603019
Pregnancy category	AU: B2 US: B (No risk in non-human studies)
Routes of administration	Oral
Legal status
Legal status	UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Bioavailability	60-68%
Protein binding	86%
Metabolism	Hepatic (CYP3A4-mediated)
Biological half-life	6.5 hours
Excretion	Fecal and renal
Identifiers
CAS Number	198904-31-3
ATC code	J05AE08 (WHO)
PubChem	CID 148192
DrugBank	DB01072
ChemSpider	130642
UNII	QZU4H47A3S
KEGG	D01276
ChEBI	CHEBI:37924
ChEMBL	CHEMBL1163
NIAID ChemDB	057755
Chemical data
Formula	C38H52N6O7
Molar mass	704.856 g/mol
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 Key:AXRYRYVKAWYZBR-GASGPIRDSA-N
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Two Reyataz 200 mg capsules

Atazanavir, sold under the trade name Reyataz, is an antiretroviral drug of the protease inhibitor (PI) class. Like other antiretrovirals, it is used to treat infection of human immunodeficiency virus (HIV).

Atazanavir is distinguished from other PIs in that it can be given once-daily (rather than requiring multiple doses per day) and has lesser effects on the patient's lipid profile (the amounts of cholesterol and other fatty substances in the blood). Like other protease inhibitors, it is used only in combination with other HIV medications.

The U.S. Food and Drug Administration (FDA) approved atazanavir on June 20, 2003. Atazanavir is the first PI approved for once-daily dosing, and also appears to be less likely to cause lipodystrophy and elevated cholesterol as side effects. It may also not be cross-resistant with other PIs. When boosted with ritonavir it is equivalent in potency to lopinavir for use in salvage therapy in patients with a degree of drug resistance, although boosting with ritonavir reduces the metabolic advantages of atazanavir.

It is on the World Health Organization's List of Essential Medicines, the most important medication needed in a basic health system.^[2]

Medical uses

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.^[3]

Adverse effects

Bilirubin levels in the blood are normally asymptomatically raised with atazanavir. A single case of torsades de pointes attributable to atazanavir therapy has been described.^[4] Atazanavir has less effect on glucose levels than ritonavir.

Contraindications

In April 2009, the US FDA issued a warning: atazanavir should not be used with proton-pump inhibitors, such as omeprazole (Prilosec), esomeprazole (Nexium), or rabeprazole (Aciphex). According to the FDA, "A 76% reduction in atazanavir area under the concentration-time curve (AUC) and a 78% reduction in atazanavir through plasma concentration (Cmin) were observed when Reyataz/ritonavir [another protease inhibitor, often prescribed with azatanavir] 300/100 mg was coadministered with omeprazole 40 mg."^[5] In other words, proton pump inhibitors reduce the absorption and effects of atazanavir due to their effect in decreasing stomach acidity.

Chemistry

Bold, Guido; Fässler, Alexander; Capraro, Hans-Georg; Cozens, Robert; Klimkait, Thomas; Lazdins, Janis; Mestan, JüRgen; Poncioni, Bernard; et al. (1998). "New Aza-Dipeptide Analogues as Potent and Orally Absorbed HIV-1 Protease Inhibitors: Candidates for Clinical Development". Journal of Medicinal Chemistry 41 (18): 3387–401. doi:10.1021/jm970873c. PMID 9719591.

Society and culture

On October 20, 2006, the FDA approved a new formulation of atazanavir (300 mg capsules) to be taken as part of combination drug therapy.^[6] This formulation should reduce pill burden, as one 300 mg capsule may replace two 150 mg capsules.

References

1. "Atazanavir". MedlinePlus. National Institutes of Health. October 15, 2012. Retrieved August 3, 2013.
2. "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
3. Croom KF, Dhillon S, Keam SJ..Drugs 2009;69(8):1107-1140. doi:10.2165/00003495-200969080-00009.
4. Ly T, Ruiz M (March 2007). "Prolonged QT interval and torsades de pointes associated with atazanavir therapy Question: Have patients developed Liver stones as a side-effect of this medication?". Clin Infect Dis 44 (6): e67–8. doi:10.1086/511875. PMID 17304444.
5. "Atazanavir, with or without ritonavir should not be coadministered with proton pump inhibitors". Food and Drug Administration. March 27, 2009. Retrieved August 26, 2013.
6. "Bristol wins U.S. approval for single anti-HIV pill". Reuters. October 20, 2006. Retrieved October 25, 2006.