Identification

Name
Fostemsavir
Accession Number
DB11796
Description

Fostemsavir is the phosphonooxymethyl prodrug of temsavir, a novel HIV-1 attachment inhibitor.5 It binds to and inhibits the activity of gp120, a subunit within the HIV-1 gp160 envelope glycoprotein that facilitates the attachment of HIV-1 to host cell CD4 receptors - in doing so, temsavir prevents the first step in the HIV-1 viral lifecycle.5 The discovery of gp120 as a potential target of interest in the treatment of HIV-1 infection is relatively recent, and was born out of a desire to find alternative target proteins (i.e. mechanistically orthogonal therapies) for the treatment of HIV-1 patients with resistant infections.3 Fostemavir is the first attachment inhibitor to receive FDA approval, granted in July 2020 for use in combination with other antiretrovirals in highly treatment-experienced patients with multidrug-resistant HIV-1 infection whom are failing their current therapy.5,7 Targeting gp120 subunits is a new and novel therapeutic approach to HIV-1 infection, and the addition of attachment inhibitors, like temsavir, to the armament of therapies targeted against HIV-1 fills a necessary niche for therapeutic options in patients left with few, if any, viable treatments.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 583.498
Monoisotopic: 583.158047823
Chemical Formula
C25H26N7O8P
Synonyms
  • Fostemsavir
External IDs
  • BMS 663068
  • BMS-663068

Pharmacology

Indication

Fostemsavir is indicated, in combination with other antiretrovirals, for the treatment of multidrug-resistant HIV-1 infection in heavily treatment-experienced adults failing their current antiretroviral therapy due to resistance, intolerance, or safety concerns.5

Associated Conditions
Contraindications & Blackbox Warnings
Learn about our commercial Contraindications & Blackbox Warnings data.
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Pharmacodynamics

Temsavir inhibits the first stage in the HIV-1 viral lifecycle: attachment.5 It has a moderate duration of action necessitating twice-daily dosing.5 Fostemsavir, administered at roughly 4x the recommended human dose, has been observed to significantly prolong the QTc-interval. Patients with a history of QTc-prolongation, those receiving other QTc-prolonging medications, and/or those with pre-existing cardiac disease should use fostemsavir with caution, and should be monitored at baseline and throughout therapy for signs or symptoms suggestive of QTc-prolongation.5 Fostemsavir should also be used with caution in patients with hepatitis B or C co-infection as elevations in hepatic transaminases were observed in greater proportions in these populations in clinical trials.5

Mechanism of action

The gp120 subunit within the gp160 envelope glycoprotein of HIV-1 is a new and novel target in the treatment of HIV-1 infection. These subunits are responsible for facilitating the first step in the viral life cycle, attachment, by mediating the interaction between the virus and host cell CD4 receptors.5,1 Following attachment, HIV-1 undergoes assembly, budding, and maturation within the host cell, after which mature viral particles are released to continue the viral life cycle.4

Fostemsavir's active metabolite, temsavir, is an HIV-1 attachment inhibitor. It binds directly to the gp120 subunit to inhibit viral interaction with host CD4 receptors, thereby preventing the initial attachment required for viral replication.5 It has also been shown to inhibit other gp120-dependent post-attachment steps required for viral entry.5

TargetActionsOrganism
AEnvelope glycoprotein gp160
inhibitor
HIV-1
Absorption

The absorption of temsavir is significantly limited by suboptimal dissolution and solubility following oral administration.3 Fostemsavir, a phosphonooxymethyl prodrug of temsavir, has improved aqueous solubility and stability under acidic conditions as compared to its parent drug - following oral administration of fostemsavir, the absolute bioavailability is approximately 26.9%.5 The Cmax and AUCtau following oral administration of fostemsavir 600mg twice daily was 1770 ng/mL and 12,900 ng.h/L, respectively, with a Tmax of approximately 2 hours.5

Co-administration of fostemsavir with a standard meal increases its AUC by approximately 10%, while co-administration with a high-fat meal increases its AUC by approximately 81%.5

Volume of distribution

The steady-state volume of distribution of temsavir following intravenous administration is approximately 29.5 L.5

Protein binding

Temsavir is approximately 88.4% protein-bound in plasma, primarily to serum albumin.5

Metabolism

Fostemsavir is rapidly hydrolyzed to temsavir, its active metabolite, by alkaline phosphatase(s) present at the brush border membrane of the intestinal lumen.3 Temsavir undergoes further biotransformation to two predominant inactive metabolites: BMS-646915, a product of hydrolysis by esterases, and BMS-930644, an N-dealkylated metabolite generated via oxidation by CYP3A4.5 Approximately 36.1% of an administered oral dose is metabolized by esterases, 21.2% is metabolized by CYP3A4, and <1% is conjugated by UDP-glucuronosyltransferases (UGT) prior to elimination.5

Both temsavir and its two predominant metabolites are known to inhibit BCRP.5

Hover over products below to view reaction partners

Route of elimination

Temsavir is highly metabolized, after which it is excreted in the urine and feces as inactive metabolites.5 Approximately 51% of a given dose is excreted in the urine, with <2% comprising unchanged parent drug, and 33% is excreted in the feces, of which 1.1% is unchanged parent drug.5

Half-life

The half-life of temsavir is approximately 11 hours.5 Fostemsavir is generally undetectable in plasma following oral administration.

Clearance

The mean clearance and apparent clearance of temsavir, the active metabolite of fostemsavir, are 17.9 L/h and 66.4 L/h, respectively.5

Adverse Effects
Learn about our commercial Adverse Effects data.
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Toxicity

Data regarding fostemsavir overdose are unavailable.5 Symptoms of overdose are likely to be consistent with fostemsavir's adverse effect profile and may therefore involve significant GI disturbance and prolongation of the QT interval.5 In the event of overdose, patients should be monitored closely, including the use of ECG, and treated symptomatically as clinically indicated. As fostemsavir is highly protein-bound, dialysis is unlikely to be of benefit in the event of an overdose.5

Affected organisms
  • HIV-1
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbametapirThe serum concentration of Fostemsavir can be increased when it is combined with Abametapir.
AbemaciclibFostemsavir may decrease the excretion rate of Abemaciclib which could result in a higher serum level.
AcebutololThe risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Acebutolol.
AcrivastineThe risk or severity of QTc prolongation can be increased when Acrivastine is combined with Fostemsavir.
AdenosineThe risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Adenosine.
AfatinibAfatinib may decrease the excretion rate of Fostemsavir which could result in a higher serum level.
AjmalineThe risk or severity of QTc prolongation can be increased when Ajmaline is combined with Fostemsavir.
AlectinibAlectinib may decrease the excretion rate of Fostemsavir which could result in a higher serum level.
AlfuzosinThe risk or severity of QTc prolongation can be increased when Alfuzosin is combined with Fostemsavir.
AlimemazineThe risk or severity of QTc prolongation can be increased when Alimemazine is combined with Fostemsavir.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions
  • Avoid St. John's Wort. The use of strong inducers of CYP3A enzymes, including St. John's Wort, is contraindicated in patients receiving fostemsavir.
  • Take with or without food. Co-administration with food slightly alters pharmacokinetics, but not to a clinically significant extent.

Products

Product Ingredients
IngredientUNIICASInChI Key
Fostemsavir tromethamine2X513P36U0864953-39-9RRGJSMBMTOKHTE-UHFFFAOYSA-N
Active Moieties
NameKindUNIICASInChI Key
Temsavirprodrug4B6J53W8N3701213-36-7QRPZBKAMSFHVRW-UHFFFAOYSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
RukobiaTablet, film coated, extended release600 mg/1OralViiV Healthcare Company2020-07-02Not applicableUS flag
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as pyridyl-1,2,4-triazoles. These are organic compounds containing a pyridine ring attached to a 1,2,4-triazole ring.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Pyridines and derivatives
Sub Class
Pyridyltriazoles
Direct Parent
Pyridyl-1,2,4-triazoles
Alternative Parents
Benzamides / Pyrrolopyridines / Aryl ketones / Benzoyl derivatives / Alkyl aryl ethers / Monoalkyl phosphates / Substituted pyrroles / Piperazines / Triazoles / Heteroaromatic compounds
show 6 more
Substituents
1,2,4-triazole / 1,4-diazinane / Alkyl aryl ether / Alkyl phosphate / Aromatic heteropolycyclic compound / Aryl ketone / Azacycle / Azole / Benzamide / Benzenoid
show 26 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Chemical Identifiers

UNII
97IQ273H4L
CAS number
864953-29-7
InChI Key
SWMDAPWAQQTBOG-UHFFFAOYSA-N
InChI
InChI=1S/C25H26N7O8P/c1-16-27-14-32(28-16)23-21-20(19(39-2)12-26-23)18(13-31(21)15-40-41(36,37)38)22(33)25(35)30-10-8-29(9-11-30)24(34)17-6-4-3-5-7-17/h3-7,12-14H,8-11,15H2,1-2H3,(H2,36,37,38)
IUPAC Name
({3-[2-(4-benzoylpiperazin-1-yl)-2-oxoacetyl]-4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl}methoxy)phosphonic acid
SMILES
COC1=CN=C(N2C=NC(C)=N2)C2=C1C(=CN2COP(O)(O)=O)C(=O)C(=O)N1CCN(CC1)C(=O)C1=CC=CC=C1

References

Synthesis Reference

Meanwell NA, Krystal MR, Nowicka-Sans B, Langley DR, Conlon DA, Eastgate MD, Grasela DM, Timmins P, Wang T, Kadow JF: Inhibitors of HIV-1 Attachment: The Discovery and Development of Temsavir and its Prodrug Fostemsavir. J Med Chem. 2018 Jan 11;61(1):62-80. doi: 10.1021/acs.jmedchem.7b01337. Epub 2017 Dec 22.

General References
  1. Meanwell NA, Krystal MR, Nowicka-Sans B, Langley DR, Conlon DA, Eastgate MD, Grasela DM, Timmins P, Wang T, Kadow JF: Inhibitors of HIV-1 Attachment: The Discovery and Development of Temsavir and its Prodrug Fostemsavir. J Med Chem. 2018 Jan 11;61(1):62-80. doi: 10.1021/acs.jmedchem.7b01337. Epub 2017 Dec 22. [PubMed:29271653]
  2. Moore K, Magee M, Sevinsky H, Chang M, Lubin S, Myers E, Ackerman P, Llamoso C: Methadone and buprenorphine pharmacokinetics and pharmacodynamics when coadministered with fostemsavir to opioid-dependent, human immunodeficiency virus seronegative participants. Br J Clin Pharmacol. 2019 Aug;85(8):1771-1780. doi: 10.1111/bcp.13964. Epub 2019 Jun 5. [PubMed:30980734]
  3. Wang T, Ueda Y, Zhang Z, Yin Z, Matiskella J, Pearce BC, Yang Z, Zheng M, Parker DD, Yamanaka GA, Gong YF, Ho HT, Colonno RJ, Langley DR, Lin PF, Meanwell NA, Kadow JF: Discovery of the Human Immunodeficiency Virus Type 1 (HIV-1) Attachment Inhibitor Temsavir and Its Phosphonooxymethyl Prodrug Fostemsavir. J Med Chem. 2018 Jul 26;61(14):6308-6327. doi: 10.1021/acs.jmedchem.8b00759. Epub 2018 Jul 13. [PubMed:29920093]
  4. Sundquist WI, Krausslich HG: HIV-1 assembly, budding, and maturation. Cold Spring Harb Perspect Med. 2012 Jul;2(7):a006924. doi: 10.1101/cshperspect.a006924. [PubMed:22762019]
  5. FDA Approved Drug Products: Rukobia (fostemsavir) extended-release tablets [Link]
  6. NIH AIDSinfo: Fostemsavir [Link]
  7. ViiV Healthcare: ViiV Healthcare announces US FDA approval for Rukobia (fostemsavir) [Link]
PubChem Compound
11319217
PubChem Substance
347828145
ChemSpider
9494181
RxNav
2380373
ChEMBL
CHEMBL3301594
ZINC
ZINC000014210883
Wikipedia
Fostemsavir

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentHuman Immunodeficiency Virus (HIV) Infections / Human Immunodeficiency Virus Infection(HIV)/Acquired Immunodeficiency Syndrome (AIDS)1
2CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections / Human Immunodeficiency Virus Type 1 (HIV-1)1
2CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections / Human Immunodeficiency Virus Type 1 (HIV-1) Infection1
1CompletedBasic ScienceHepatic Impairment1
1CompletedBasic ScienceHuman Immunodeficiency Virus (HIV) Infections / Human Immunodeficiency Virus Infection(HIV)/Acquired Immunodeficiency Syndrome (AIDS)1
1CompletedHealth Services ResearchHuman Immunodeficiency Virus (HIV) Infections / Human Immunodeficiency Virus Infection(HIV)/Acquired Immunodeficiency Syndrome (AIDS)1
1CompletedOtherHuman Immunodeficiency Virus (HIV) Infections2
1CompletedOtherHuman Immunodeficiency Virus (HIV) Infections / Human Immunodeficiency Virus Infection(HIV)/Acquired Immunodeficiency Syndrome (AIDS)3
1CompletedTreatmentDrug-drug Interaction Study / Human Immunodeficiency Virus (HIV) Infections1
1CompletedTreatmentEnd Stage Renal Disease (ESRD) / Human Immunodeficiency Virus (HIV) Infections / Impaired kidney function1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Tablet, film coated, extended releaseOral600 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US8461333No2005-02-252025-02-25US flag
US8168615No2005-02-252025-02-25US flag
US7745625No2007-11-192027-11-19US flag
Additional Data Available
  • Filed On
    Filed On

    The date on which a patent was filed with the relevant government.

    Learn more

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubility>250mg/mLFDA Label
Predicted Properties
PropertyValueSource
Water Solubility0.431 mg/mLALOGPS
logP0.64ALOGPS
logP-0.13ChemAxon
logS-3.1ALOGPS
pKa (Strongest Acidic)1.75ChemAxon
pKa (Strongest Basic)0.97ChemAxon
Physiological Charge-2ChemAxon
Hydrogen Acceptor Count10ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area182.21 Å2ChemAxon
Rotatable Bond Count8ChemAxon
Refractivity145.6 m3·mol-1ChemAxon
Polarizability55.13 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
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

Targets

Kind
Protein
Organism
HIV-1
Pharmacological action
Yes
Actions
Inhibitor
General Function
Structural molecule activity
Specific Function
Envelope glycoprotein gp160: Oligomerizes in the host endoplasmic reticulum into predominantly trimers. In a second time, gp160 transits in the host Golgi, where glycosylation is completed. The pre...
Gene Name
env
Uniprot ID
P12488
Uniprot Name
Envelope glycoprotein gp160
Molecular Weight
97202.505 Da
References
  1. FDA Approved Drug Products: Rukobia (fostemsavir) extended-release tablets [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. FDA Approved Drug Products: Rukobia (fostemsavir) extended-release tablets [Link]
Kind
Protein group
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the...

Components:
References
  1. FDA Approved Drug Products: Rukobia (fostemsavir) extended-release tablets [Link]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Carrier
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. FDA Approved Drug Products: Rukobia (fostemsavir) extended-release tablets [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. FDA Approved Drug Products: Rukobia (fostemsavir) extended-release tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
Molecular Weight
72313.47 Da
References
  1. FDA Approved Drug Products: Rukobia (fostemsavir) extended-release tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostagland...
Gene Name
SLCO1B1
Uniprot ID
Q9Y6L6
Uniprot Name
Solute carrier organic anion transporter family member 1B1
Molecular Weight
76447.99 Da
References
  1. FDA Approved Drug Products: Rukobia (fostemsavir) extended-release tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as 17-beta-glucuronosyl estradiol, taurocholate, triiodothyronine (T3), leukotriene C4, dehydroepiandrosterone sulfate (DHEAS), methotre...
Gene Name
SLCO1B3
Uniprot ID
Q9NPD5
Uniprot Name
Solute carrier organic anion transporter family member 1B3
Molecular Weight
77402.175 Da
References
  1. FDA Approved Drug Products: Rukobia (fostemsavir) extended-release tablets [Link]

Drug created on October 20, 2016 14:48 / Updated on July 10, 2020 21:43

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