Tenofovir alafenamide

Tenofovir alafenamide

Clinical data
Trade names	Genvoya (with elvitegravir, cobicistat and emtricitabine) Odefsey (with emtricitabine and rilpivirine) Descovy (with emtricitabine)
Routes of administration	Oral (tablets)
ATC code	J05AR17 (WHO) J05AR18 (WHO) J05AR19 (WHO) (combination codes)
Legal status
Legal status	℞ (Prescription only)
Pharmacokinetic data
Protein binding	~80%[1]
Biological half-life	0.51 hours
Excretion	Feces (31.7%), urine (<1%)
Identifiers
IUPAC name Isopropyl (2S)-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphoryl]amino]propanoate
CAS Number	379270-37-8
PubChem (CID)	9574768
DrugBank	DB09299
ChemSpider	7849225
UNII	EL9943AG5J
KEGG	D10428
ChEBI	CHEBI:90926
ChEMBL	CHEMBL2107825
Chemical and physical data
Formula	C21H29N6O5P
Molar mass	476.466 g/mol
3D model (Jmol)	Interactive image
SMILES C[C@H](CN1C=NC2=C(N=CN=C21)N)OC[P@@](=O)(N[C@@H](C)C(=O)OC(C)C)OC3=CC=CC=C3
InChI InChI=1S/C21H29N6O5P/c1-14(2)31-21(28)16(4)26-33(29,32-17-8-6-5-7-9-17)13-30-15(3)10-27-12-25-18-19(22)23-11-24-20(18)27/h5-9,11-12,14-16H,10,13H2,1-4H3,(H,26,29)(H2,22,23,24)/t15-,16+,33+/m1/s1 Key:LDEKQSIMHVQZJK-CAQYMETFSA-N

Tenofovir alafenamide fumarate, the salt used in drug formulations.

Tenofovir alafenamide (INN/USAN, formerly GS-7340) is a nucleotide reverse transcriptase inhibitor and a prodrug of tenofovir. It was developed by Gilead Sciences for use in the treatment of HIV infection and chronic hepatitis B, and is applied in the form of tenofovir alafenamide fumarate (TAF). Closely related to the commonly used reverse-transcriptase inhibitor tenofovir disoproxil, TAF has greater antiviral activity and better distribution into lymphoid tissues than that agent.^[2][3]

Gilead announced a phase 3 clinical trial evaluating a single-tablet regimen combining tenofovir alafenamide with cobicistat, emtricitabine and elvitegravir^[4] and developed a coformulation of the drug with cobicistat, emtricitabine and the protease inhibitor darunavir.^[5][6][7] In a 48-week study comparing elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil to elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (trade name Genvoya), the results showed the newer drug to be noninferior to the established agent, but at much lower dosages and with lower incidence of adverse side effects such as impaired kidney function.^[8][9][10] The FDA approved the TAF-based treatment regimen for treatment of HIV-1 in November 2015.^[11] Genvoya is the first TAF-based regimen to receive approval.^[11]

Fixed-dose combinations containing tenofovir alafenamide

• Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (trade name Genvoya) — approved November 5, 2015 (compare Elvitegravir/cobicistat/emtricitabine/tenofovir; trade name Stribild)
• Emtricitabine/rilpivirine/tenofovir alafenamide (trade name Odefsey)^[12] — approved March 1, 2016 (compare Emtricitabine/rilpivirine/tenofovir; trade name Complera)
• Emtricitabine/tenofovir alafenamide (trade name Descovy)^[13] — approved April 4, 2016 (compare Emtricitabine/tenofovir; trade name Truvada)

See also

• Sofosbuvir — an HCV RNA polymerase (NS5B) inhibitor bearing structural similarity (phosphoramidate side chain metabolized by cathepsin A, carboxylesterase 1 and histidine triad nucleotide-binding protein 1)^[14][15]

References

1. "GENVOYA (elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide) Tablets, for Oral Use. Full Prescribing Information" (PDF). Gilead Sciences, Inc. Foster City, CA 94404.
2. Eisenberg, E. J.; He, G. X.; Lee, W. A. (2001). "Metabolism of Gs-7340, A Novel Phenyl Monophosphoramidate Intracellular Prodrug of Pmpa, in Blood". Nucleosides, Nucleotides and Nucleic Acids. 20 (4–7): 1091–1098. doi:10.1081/NCN-100002496. PMID 11562963.
3. M Markowitz, A Zolopa, et al. GS-7340 Demonstrates Greater Declines in HIV-1 RNA than Tenofovir Disoproxil Fumarate During 14 Days of Monotherapy in HIV-1 Infected Subjects. 18th Conference on Retroviruses and Opportunistic Infections 2 Mar 2011. Paper # 152LB
4. "Gilead Initiates Phase 3 Clinical Program for Tenofovir Alafenamide" (Press release). Gilead. January 2013.
5. McQueen, Courtney (16 Nov 2011). "Gilead And Tibotec To Develop Single-Pill Protease Inhibitor-Based Combination Regimen". The AIDS Beacon.
6. GS-7340 Packs Greater HIV Punch, Potentially Better Safety, Versus Viread Horn, Tim. 15 Mar 2012. AIDSmeds.com
7. Pharmacokinetics of a Novel EVG/COBI/FTC/GS-7340 Single Tablet Regimen. 13th International Workshop on Clinical Pharmacology of HIV Therapy. Barcelona, Spain. April 16–18, 2012.
8. Once-Daily Tenofovir Prodrug Combo Pill as Effective as Stribild. AIDSmeds.com 1 Nov 2012.
9. CROI 2013: New Pro-drug Tenofovir Alafenamide Appears Equally Effective but Better Tolerated. Highleyman, Liz. HIVandHepatitis.com. 6 March 2013.
10. Horn, T. et al. Tenefovir Alafenamide Fumarate (TAF) Sign-On Letter to Gilead. 13 June 2013. Treatment Action Group.
11. "U.S. Food and Drug Administration Approves Gilead's Single Tablet Regimen Genvoya (Elvitegravir, Cobicistat, Emtricitabine and Tenofovir Alafenamide) for Treatment of HIV-1 Infection". Gilead. 5 November 2015.
12. "Odefsey (emtricitabine, rilpivirine, and tenofovir alafenamide) Tablets, for Oral Use. U.S. Full Prescribing Information" (PDF). Gilead Sciences, Inc. Retrieved 2 March 2016.
13. "Descovy (emtricitabine and tenofovir alafenamide) Tablets, for Oral Use. U.S. Full Prescribing Information" (PDF). Gilead Sciences, Inc. Retrieved 5 April 2016.
14. "Comparison of tenofovir prodrugs: TAF vs TDF". DRUG R&D INSIGHT. Retrieved 24 November 2015.
15. Murakami, E.; Tolstykh, T.; Bao, H.; Niu, C.; Steuer, H. M. M.; Bao, D.; Chang, W.; Espiritu, C.; Bansal, S.; Lam, A. M.; Otto, M. J.; Sofia, M. J.; Furman, P. A. (26 August 2010). "Mechanism of Activation of PSI-7851 and Its Diastereoisomer PSI-7977". Journal of Biological Chemistry. 285 (45): 34337–34347. doi:10.1074/jbc.M110.161802.