Tenofovir alafenamide

Identification

Name
Tenofovir alafenamide
Accession Number
DB09299
Type
Small Molecule
Groups
Approved
Description

Tenofovir alafenamide fumarate (TAF) is a nucleotide reverse transcriptase inhibitor (NRTI) and a novel ester prodrug of the antiretroviral tenofovir. Following oral administration, TAF is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5′-monophosphate. Tenofovir mimics normal DNA building blocks but is lacking a 3'-OH molecule required for phosphodiester bond linkage. By competing with regular nucleotides for incorporation into proviral DNA and prevention of the formation of the 5' to 3' phosphodiester linkage required for DNA elongation, tenofovir causes early chain termination and prevents proviral DNA transcription.

Although tenofovir (available as tenofovir disoproxil fumarate) has a good safety profile and efficacy, and is currently a cornerstone of HIV antiviral treatment, its use has been associated with nephrotoxicity and reduced bone mineral density. In comparison, TAF has been shown to have improved antiviral efficacy, enhanced delivery of TFV into peripheral blood mononuclear cells (PBMCs) and lymphatic tissues, a higher barrier to resistance, and an improved safety profile. Improved renal safety is likely attributable to lower circulating plasma concentrations of tenofovir and therefore less exposure and damage to bone and the kidneys, where tenofovir is metabolized. Because HIV antiretroviral therapy is usually life-long, reduced toxicity and improved efficacy results in better patient outcomes and improved adherence in the long term.

Tenofovir alafenamide fumarate is currently available in two fixed dose combination products: Odefsey (emtricitabine, rilpivirine, and tenofovir alafenamide), and Descovy (emtricitabine and tenofovir alafenamide). Both products are indicated for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older.

Structure
Thumb
Synonyms
Not Available
External IDs
GS 7340 / GS 7340 03 / GS 734003 / GS-7340 / GS-7340-03 / GS-734003 / GS7340 / GS734003
Product Ingredients
IngredientUNIICASInChI Key
Tenofovir alafenamide fumarateFWF6Q91TZO1392275-56-7SVUJNSGGPUCLQZ-FQQAACOVSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
VemlidyTablet25 mgOralGilead Sciences2017-06-20Not applicableCanada
VemlidyTablet25 mg/1OralGilead Sciences2016-11-10Not applicableUs
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
BiktarvyTenofovir alafenamide fumarate (25 mg/1) + Bictegravir sodium (50 mg/1) + Emtricitabine (200 mg/1)TabletOralGilead Sciences2018-02-07Not applicableUs
DescovyTenofovir alafenamide (25 mg/1) + Emtricitabine (200 mg/1)TabletOralRemedy Repack2017-02-16Not applicableUs
DescovyTenofovir alafenamide (25 mg) + Emtricitabine (200 mg)TabletOralGilead Sciences2016-06-03Not applicableCanada
DescovyTenofovir alafenamide fumarate (25 mg/1) + Emtricitabine (200 mg/1)TabletOralGilead Sciences2016-04-04Not applicableUs
DescovyTenofovir alafenamide (10 mg) + Emtricitabine (200 mg)TabletOralGilead Sciences2016-06-03Not applicableCanada
GenvoyaTenofovir alafenamide (10 mg) + Cobicistat (150 mg) + Elvitegravir (150 mg) + Emtricitabine (200 mg)TabletOralGilead Sciences2016-02-03Not applicableCanada
GenvoyaTenofovir alafenamide (10 mg) + Cobicistat (150 mg) + Elvitegravir (150 mg) + Emtricitabine (200 mg)Tablet, film coatedOralGilead Sciences2015-11-19Not applicableEu
GenvoyaTenofovir alafenamide fumarate (10 mg/1) + Cobicistat (150 mg/1) + Elvitegravir (150 mg/1) + Emtricitabine (200 mg/1)TabletOralGilead Sciences2015-11-05Not applicableUs
GenvoyaTenofovir alafenamide (10 mg) + Cobicistat (150 mg) + Elvitegravir (150 mg) + Emtricitabine (200 mg)Tablet, film coatedOralGilead Sciences2015-11-19Not applicableEu
GenvoyaTenofovir alafenamide (10 mg/1) + Cobicistat (150 mg/1) + Elvitegravir (150 mg/1) + Emtricitabine (200 mg/1)TabletOralRemedy Repack2017-06-06Not applicableUs
Categories
UNII
J4414G3BUK
CAS number
379270-37-8
Weight
Average: 476.474
Monoisotopic: 476.193705056
Chemical Formula
C21H29N6O5P
InChI Key
LDEKQSIMHVQZJK-CAQYMETFSA-N
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
IUPAC Name
propan-2-yl (2S)-2-{[(S)-({[(2R)-1-(6-amino-9H-purin-9-yl)propan-2-yl]oxy}methyl)(phenoxy)phosphoryl]amino}propanoate
SMILES
CC(C)OC(=O)[C@H](C)N[P@](=O)(CO[C@H](C)CN1C=NC2=C(N)N=CN=C12)OC1=CC=CC=C1

Pharmacology

Indication

For use in the treatment of HIV infection and chronic hepatitis B.

Associated Conditions
Pharmacodynamics

In a thorough QT/QTc study in 48 healthy subjects, TAF at the recommended dose and at a dose approximately 5 times the recommended dose, did not affect the QT/QTc interval and did not prolong the PR interval.

Mechanism of action

Tenofovir alafenamide fumarate (TAF) is a nucleotide reverse transcriptase inhibitor (NRTI) and a novel ester prodrug of the antiretroviral tenofovir. Following oral administration, TAF is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5′-monophosphate. Tenofovir mimics normal DNA building blocks but is lacking a 3'-OH molecule required for phosphodiester bond linkage. By competing with regular nucleotides for incorporation into proviral DNA and prevention of the formation of the 5' to 3' phosphodiester linkage required for DNA elongation, tenofovir causes early chain termination and prevents proviral DNA transcription.

TargetActionsOrganism
AReverse transcriptase/RNaseH
inhibitor
Human immunodeficiency virus 1
Absorption

Tmax is observed at 1 hour post oral administration.

Volume of distribution
Not Available
Protein binding

Tenofovir alafenamide fumarate is ~80% bound to human plasma proteins.

Metabolism

In vivo, TAF is hydrolyzed within cells to form tenofovir (major metabolite), which is phosphorylated to the active metabolite, tenofovir diphosphate. In vitro studies have shown that TAF is metabolized to tenofovir by cathepsin A (also known as Lysosomal Protective Protein) in peripheral blood mononuclear cells (PBMCs) and macrophages; and by Carboxylesterase 1 (CES1) in hepatocytes.

Route of elimination
Not Available
Half life

0.51 h

Clearance
Not Available
Toxicity
Not Available
Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteractionDrug group
BacitracinThe serum concentration of Tenofovir alafenamide can be increased when it is combined with Bacitracin.Approved, Vet Approved
CyclosporineThe serum concentration of Tenofovir alafenamide can be increased when it is combined with Cyclosporine.Approved, Investigational, Vet Approved
DiclofenacThe serum concentration of Tenofovir alafenamide can be increased when it is combined with Diclofenac.Approved, Vet Approved
IbuprofenThe serum concentration of Tenofovir alafenamide can be increased when it is combined with Ibuprofen.Approved
NaproxenThe serum concentration of Tenofovir alafenamide can be increased when it is combined with Naproxen.Approved, Vet Approved
NeomycinThe serum concentration of Tenofovir alafenamide can be increased when it is combined with Neomycin.Approved, Vet Approved
NimesulideThe serum concentration of Tenofovir alafenamide can be increased when it is combined with Nimesulide.Approved, Investigational, Withdrawn
Salicylic acidThe serum concentration of Tenofovir alafenamide can be increased when it is combined with Salicylic acid.Approved, Investigational, Vet Approved
SulfasalazineThe serum concentration of Tenofovir alafenamide can be increased when it is combined with Sulfasalazine.Approved
Tolfenamic AcidThe serum concentration of Tenofovir alafenamide can be increased when it is combined with Tolfenamic Acid.Approved, Investigational
Trolamine salicylateThe serum concentration of Tenofovir alafenamide can be increased when it is combined with Trolamine salicylate.Approved
Food Interactions
Not Available

References

General References
  1. Gibson AK, Shah BM, Nambiar PH, Schafer JJ: Tenofovir Alafenamide: A Review of Its Use in the Treatment of HIV-1 Infection. Ann Pharmacother. 2016 Jul 26. pii: 1060028016660812. [PubMed:27465879]
  2. Ruane PJ, DeJesus E, Berger D, Markowitz M, Bredeek UF, Callebaut C, Zhong L, Ramanathan S, Rhee MS, Fordyce MW, Yale K: Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of tenofovir alafenamide as 10-day monotherapy in HIV-1-positive adults. J Acquir Immune Defic Syndr. 2013 Aug 1;63(4):449-55. doi: 10.1097/QAI.0b013e3182965d45. [PubMed:23807155]
  3. Ray AS, Fordyce MW, Hitchcock MJ: Tenofovir alafenamide: A novel prodrug of tenofovir for the treatment of Human Immunodeficiency Virus. Antiviral Res. 2016 Jan;125:63-70. doi: 10.1016/j.antiviral.2015.11.009. Epub 2015 Nov 27. [PubMed:26640223]
  4. Bam RA, Birkus G, Babusis D, Cihlar T, Yant SR: Metabolism and antiretroviral activity of tenofovir alafenamide in CD4+ T-cells and macrophages from demographically diverse donors. Antivir Ther. 2014;19(7):669-77. doi: 10.3851/IMP2767. Epub 2014 Mar 14. [PubMed:24625459]
  5. Eisenberg EJ, He GX, Lee WA: Metabolism of GS-7340, a novel phenyl monophosphoramidate intracellular prodrug of PMPA, in blood. Nucleosides Nucleotides Nucleic Acids. 2001 Apr-Jul;20(4-7):1091-8. [PubMed:11562963]
  6. Bam RA, Yant SR, Cihlar T: Tenofovir alafenamide is not a substrate for renal organic anion transporters (OATs) and does not exhibit OAT-dependent cytotoxicity. Antivir Ther. 2014;19(7):687-92. doi: 10.3851/IMP2770. Epub 2014 Apr 4. [PubMed:24699134]
  7. Birkus G, Wang R, Liu X, Kutty N, MacArthur H, Cihlar T, Gibbs C, Swaminathan S, Lee W, McDermott M: Cathepsin A is the major hydrolase catalyzing the intracellular hydrolysis of the antiretroviral nucleotide phosphonoamidate prodrugs GS-7340 and GS-9131. Antimicrob Agents Chemother. 2007 Feb;51(2):543-50. Epub 2006 Dec 4. [PubMed:17145787]
External Links
KEGG Drug
D10428
PubChem Compound
9574768
PubChem Substance
310265191
ChemSpider
7849225
ChEBI
90926
ChEMBL
CHEMBL2107825
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Tenofovir_alafenamide
ATC Codes
J05AR19 — Emtricitabine, tenofovir alafenamide and rilpivirineJ05AR18 — Emtricitabine, tenofovir alafenamide, elvitegravir and cobicistatJ05AR17 — Emtricitabine and tenofovir alafenamide
AHFS Codes
  • 08:18.08.20 — Nucleoside and Nucleotide Reverse Transcriptase Inhibitors
FDA label
Download (1.08 MB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedHealth Services ResearchHuman Immunodeficiency Virus (HIV)1
1CompletedPreventionHealthy Volunteers1
1CompletedPreventionHuman Immunodeficiency Virus (HIV)1
1CompletedTreatmentHealthy Volunteers2
1CompletedTreatmentHepatitis B Chronic Infection1
1CompletedTreatmentHepatitis B Virus (HBV)1
1RecruitingBasic ScienceHealthy Volunteers1
1RecruitingOtherHealthy Volunteers1
1RecruitingPreventionHuman Immunodeficiency Virus (HIV) Infections1
1RecruitingTreatmentInsulin Resistance1
1, 2CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections1
2Active Not RecruitingTreatmentHepatitis B Chronic Infection1
2Active Not RecruitingTreatmentInfection, Human Immunodeficiency Virus I1
2CompletedTreatmentAcquired Immune Deficiency Syndrome (AIDS) / Human Immunodeficiency Virus (HIV) Infections2
2Not Yet RecruitingTreatmentHepatitis B Chronic Infection1
2Not Yet RecruitingTreatmentHuman Immunodeficiency Virus (HIV) Infections1
2RecruitingTreatmentHIV and Hepatitis B Coinfection1
2RecruitingTreatmentHepatitis B Chronic Infection4
2RecruitingTreatmentHuman Immunodeficiency Virus (HIV)1
2TerminatedTreatmentHBV / Human Immunodeficiency Virus (HIV)1
2, 3Active Not RecruitingTreatmentAcquired Immune Deficiency Syndrome (AIDS) / Human Immunodeficiency Virus (HIV) Infections1
2, 3Active Not RecruitingTreatmentInfection, Human Immunodeficiency Virus I1
2, 3CompletedTreatmentHuman Immunodeficiency Virus (HIV)1
2, 3RecruitingTreatmentHuman Immunodeficiency Virus Type 1 (HIV-1)1
3Active Not RecruitingTreatmentAcquired Immune Deficiency Syndrome (AIDS) / Human Immunodeficiency Virus (HIV) Infections1
3Active Not RecruitingTreatmentAcquired Immune Deficiency Syndrome (AIDS) / Human Immunodeficiency Virus (HIV) / Human Immunodeficiency Virus (HIV) Infections1
3Active Not RecruitingTreatmentChronic HBV Infections / Chronic Infection With HIV / HBV1
3Active Not RecruitingTreatmentChronic HBV Infections / HBV3
3Active Not RecruitingTreatmentChronic Hepatitis C Virus (HCV) Infection / Human Immunodeficiency Virus (HIV)1
3Active Not RecruitingTreatmentHIV-1-infection2
3Active Not RecruitingTreatmentHepatitis B Chronic Infection1
3Active Not RecruitingTreatmentHuman Immunodeficiency Virus (HIV) / Human Immunodeficiency Virus (HIV) Infections3
3Active Not RecruitingTreatmentHuman Immunodeficiency Virus Type 1 (HIV-1)1
3Active Not RecruitingTreatmentInfection, Human Immunodeficiency Virus I11
3Active Not RecruitingTreatmentPre-Exposure Prophylaxis of HIV-1 Infection1
3CompletedTreatmentAcquired Immune Deficiency Syndrome (AIDS) / Human Immunodeficiency Virus (HIV) Infections / Human Immunodeficiency Virus Type 1 (HIV-1)1
3CompletedTreatmentHBV / Human Immunodeficiency Virus (HIV)1
3CompletedTreatmentHCV Infections / Infection, Human Immunodeficiency Virus I1
3CompletedTreatmentHuman Immunodeficiency Virus (HIV) / Human Immunodeficiency Virus (HIV) Infections1
3CompletedTreatmentInfection, Human Immunodeficiency Virus I1
3Enrolling by InvitationTreatmentHIV Risk1
3RecruitingTreatmentHIV-1/HBV Co-Infection1
3RecruitingTreatmentHuman Immunodeficiency Virus (HIV) Infections1
3RecruitingTreatmentInfection, Human Immunodeficiency Virus I2
4Active Not RecruitingTreatmentHuman Immunodeficiency Virus (HIV)1
4Active Not RecruitingTreatmentViral Hepatitis B1
4CompletedOtherHuman Immunodeficiency Virus (HIV)1
4Not Yet RecruitingTreatmentHIV-1-infection1
4Not Yet RecruitingTreatmentHepatitis B Chronic Infection1
4Not Yet RecruitingTreatmentHuman Immunodeficiency Virus (HIV) Infections1
4Not Yet RecruitingTreatmentBone destruction / Human Immunodeficiency Virus (HIV) / Menopause1
4Not Yet RecruitingTreatmentViral Hepatitis B1
4RecruitingTreatmentBone Diseases, Metabolic / Chronic Hepatitis C Virus (HCV) Infection / Co-Infection / Drug Abuse / HIV-1-infection / Human Immunodeficiency Virus Infection(HIV)/Acquired Immunodeficiency Syndrome (AIDS) / Intravenous Drug Usage / Methadone Dependence / Opioid Dependence1
4RecruitingTreatmentHepatitis B Chronic Infection2
4RecruitingTreatmentHuman Immunodeficiency Virus (HIV)1
4RecruitingTreatmentHuman Immunodeficiency Virus (HIV) Infections2
4RecruitingTreatmentHuman Immunodeficiency Virus (HIV) / Renal Insufficiency,Chronic / Therapeutic Agent Toxicity1
Not AvailableCompletedTreatmentHuman Immunodeficiency Virus (HIV)1
Not AvailableNot Yet RecruitingNot AvailableAntiviral Drug Adverse Reaction / Viral Hepatitis B1
Not AvailableNot Yet RecruitingNot AvailableHIV-1-infection1
Not AvailableNot Yet RecruitingNot AvailableHepatitis B Chronic Infection1
Not AvailableNot Yet RecruitingTreatmentHuman Immunodeficiency Virus Infection(HIV)/Acquired Immunodeficiency Syndrome (AIDS)1
Not AvailableRecruitingNot AvailableBone Diseases / Chronic Hepatitis B in HIV Patient / Kidney Injury1
Not AvailableRecruitingNot AvailableHepatitis B, Chronic / Hepatitis C Viral Infection1
Not AvailableRecruitingNot AvailableHuman Immunodeficiency Virus (HIV)2
Not AvailableRecruitingTreatmentHuman Immunodeficiency Virus (HIV) Infections1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
TabletOral
Tablet, film coatedOral
TabletOral25 mg/1
TabletOral25 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US7800788No2002-02-022022-02-02Us
US5914331Yes1998-01-022018-01-02Us
US5814639Yes1997-03-292017-03-29Us
US6642245Yes2001-05-042021-05-04Us
US6703396Yes2001-09-092021-09-09Us
US7125879No2002-08-092022-08-09Us
US6838464No2001-02-262021-02-26Us
US8080551No2003-04-112023-04-11Us
US8101629No2002-08-092022-08-09Us
US7067522No1999-12-202019-12-20Us
US8148374No2009-09-032029-09-03Us
US7635704No2006-10-262026-10-26Us
US7176220No2003-11-202023-11-20Us
US8981103No2006-10-262026-10-26Us
US8633219No2010-04-242030-04-24Us
US9296769No2012-08-152032-08-15Us
US7803788No2002-02-022022-02-02Us
US8754065No2012-08-152032-08-15Us
US7390791No2002-05-072022-05-07Us
US9891239No2009-09-032029-09-03Us
US9216996No2013-12-192033-12-19Us
US9708342No2015-06-192035-06-19Us
US9732092No2013-12-192033-12-19Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubility4.86 mg/mLDPD Monograph
logP1.6DPD Monograph
pKa3.96DPD Monograph
Predicted Properties
PropertyValueSource
Water Solubility0.236 mg/mLALOGPS
logP1.49ALOGPS
logP1.88ChemAxon
logS-3.3ALOGPS
pKa (Strongest Acidic)11.36ChemAxon
pKa (Strongest Basic)5.12ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count7ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area143.48 Å2ChemAxon
Rotatable Bond Count12ChemAxon
Refractivity122.74 m3·mol-1ChemAxon
Polarizability47.88 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as alpha amino acid esters. These are ester derivatives of alpha amino acids.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
Alpha amino acid esters
Alternative Parents
Alanine and derivatives / 6-aminopurines / Phenoxy compounds / Aminopyrimidines and derivatives / Phosphonic amide esters / Phosphonic acid esters / N-substituted imidazoles / Imidolactams / Heteroaromatic compounds / Carboxylic acid esters
show 8 more
Substituents
Alpha-amino acid ester / Alanine or derivatives / 6-aminopurine / Purine / Imidazopyrimidine / Phenoxy compound / Aminopyrimidine / Phosphonic acid ester / Monocyclic benzene moiety / N-substituted imidazole
show 24 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human immunodeficiency virus 1
Pharmacological action
Yes
Actions
Inhibitor
General Function
Rna-dna hybrid ribonuclease activity
Specific Function
Not Available
Gene Name
pol
Uniprot ID
Q72547
Uniprot Name
Reverse transcriptase/RNaseH
Molecular Weight
65223.615 Da

Drug created on November 08, 2015 14:16 / Updated on August 13, 2018 10:11