Identification
- Summary
Fostemsavir is an antiretroviral HIV-1 attachment inhibitor targeted against the gp120 subunit within the HIV-1 gp160 envelope glycoprotein.
- Brand Names
- Rukobia
- Generic Name
- Fostemsavir
- DrugBank Accession Number
- DB11796
- Background
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
Structure for Fostemsavir (DB11796)
- 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
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Used in combination to treat Human immunodeficiency virus type 1 (hiv-1) infection •••••••••••• ••••• ••••••• ••••••• •••••••••••••• •••••••• •••••••••••••• •••••••••••••••••••••• ••••••••• ••••••••• ••••• ••••••••• ••••••• •••••••• ••••••• - Contraindications & Blackbox Warnings
Prevent Adverse Drug Events TodayTap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events with our Clinical API- 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
Target Actions Organism AEnvelope glycoprotein gp160 inhibitorHIV-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
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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
- 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.
Drug Interaction Integrate drug-drug
interactions in your softwareAbametapir The serum concentration of Fostemsavir can be increased when it is combined with Abametapir. Abemaciclib Fostemsavir may decrease the excretion rate of Abemaciclib which could result in a higher serum level. Abrocitinib The serum concentration of Fostemsavir can be increased when it is combined with Abrocitinib. Acrivastine The risk or severity of QTc prolongation can be increased when Acrivastine is combined with Fostemsavir. Adagrasib The serum concentration of Fostemsavir can be increased when it is combined with Adagrasib. - 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
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Product Ingredients
Ingredient UNII CAS InChI Key Fostemsavir tromethamine 2X513P36U0 864953-39-9 RRGJSMBMTOKHTE-UHFFFAOYSA-N - Active Moieties
Name Kind UNII CAS InChI Key Temsavir prodrug 4B6J53W8N3 701213-36-7 QRPZBKAMSFHVRW-UHFFFAOYSA-N - Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Rukobia Tablet, extended release 600 mg Oral Vii V Healthcare B.V. 2021-03-16 Not applicable EU 
Rukobia Tablet, extended release 600 mg Oral ViiV Healthcare ULC 2022-04-26 Not applicable Canada 
Rukobia Tablet, extended release 600 mg Oral Vii V Healthcare B.V. 2021-04-20 Not applicable EU Rukobia Tablet, film coated, extended release 600 mg/1 Oral ViiV Healthcare Company 2020-07-02 Not applicable US 
Categories
- ATC Codes
- J05AX29 — Fostemsavir
- Drug Categories
- Anti-HIV Agents
- Anti-Infective Agents
- Anti-Retroviral Agents
- Antiinfectives for Systemic Use
- Antiviral Agents
- Antivirals for Systemic Use
- BCRP/ABCG2 Inhibitors
- BCRP/ABCG2 Substrates
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 Substrates
- Direct Acting Antivirals
- HIV Fusion Inhibitors
- Human Immunodeficiency Virus Type 1 (HIV-1) gp120-directed Attachment Inhibitors
- OATP1B1/SLCO1B1 Inhibitors
- OATP1B3 inhibitors
- Organophosphorus Compounds
- P-glycoprotein substrates
- Potential QTc-Prolonging Agents
- QTc Prolonging Agents
- Viral Fusion Protein Inhibitors
- 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
- Affected organisms
- HIV-1
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
- 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. [Article]
- 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. [Article]
- 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. [Article]
- 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. [Article]
- FDA Approved Drug Products: Rukobia (fostemsavir) extended-release tablets [Link]
- NIH AIDSinfo: Fostemsavir [Link]
- ViiV Healthcare: ViiV Healthcare announces US FDA approval for Rukobia (fostemsavir) [Link]
- External Links
- PubChem Compound
- 11319217
- PubChem Substance
- 347828145
- ChemSpider
- 9494181
- 2380373
- ChEMBL
- CHEMBL3301594
- ZINC
- ZINC000014210883
- Wikipedia
- Fostemsavir
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 4 Recruiting Treatment Human Immunodeficiency Virus Type 1 (HIV-1) Infection 1 3 Active Not Recruiting Treatment Human Immunodeficiency Virus (HIV) Infections 1 2 Completed Treatment Human Immunodeficiency Virus (HIV) Infections 2 1 Completed Basic Science Human Immunodeficiency Virus (HIV) Infections 2 1 Completed Health Services Research Human Immunodeficiency Virus (HIV) Infections 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet Oral 600.00 mg Tablet, extended release Oral 600 mg Tablet, film coated, extended release Oral 600 mg/1 - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US8461333 No 2013-06-11 2025-02-25 US US8168615 No 2012-05-01 2025-02-25 US US7745625 No 2010-06-29 2027-11-19 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source water solubility >250mg/mL FDA Label - Predicted Properties
Property Value Source Water Solubility 0.431 mg/mL ALOGPS logP 0.64 ALOGPS logP -0.13 Chemaxon logS -3.1 ALOGPS pKa (Strongest Acidic) 1.75 Chemaxon pKa (Strongest Basic) 0.97 Chemaxon Physiological Charge -2 Chemaxon Hydrogen Acceptor Count 10 Chemaxon Hydrogen Donor Count 2 Chemaxon Polar Surface Area 182.21 Å2 Chemaxon Rotatable Bond Count 8 Chemaxon Refractivity 145.6 m3·mol-1 Chemaxon Polarizability 55.13 Å3 Chemaxon Number of Rings 5 Chemaxon Bioavailability 1 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 265.1150302 predictedDarkChem Lite v0.1.0 [M-H]- 214.58687 predictedDeepCCS 1.0 (2019) [M+H]+ 264.7844302 predictedDarkChem Lite v0.1.0 [M+H]+ 216.55864 predictedDeepCCS 1.0 (2019) [M+Na]+ 264.4969302 predictedDarkChem Lite v0.1.0 [M+Na]+ 222.29907 predictedDeepCCS 1.0 (2019)
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
- 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
- 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
- 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
- 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
- FDA Approved Drug Products: Rukobia (fostemsavir) extended-release tablets [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- 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
- 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
- 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
- FDA Approved Drug Products: Rukobia (fostemsavir) extended-release tablets [Link]
Drug created at October 20, 2016 20:48 / Updated at February 21, 2021 18:53