Peringatan Keamanan

Data regarding fostemsavir overdose are unavailable.^L14867 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.^L14867 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.^L14867

Fostemsavir

DB11796

small molecule approved investigational

Deskripsi

Fostemsavir is the phosphonooxymethyl prodrug of temsavir, a novel HIV-1 attachment inhibitor.^L14867 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.^L14867 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.^A215057 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.L14867,L14917 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.

Struktur Molekul 2D

Berat 583.498

Wujud solid

Peta Jejaring Molekuler

Obat Target Gen Interaksi Enzim Transporter Carrier

Legenda: Obat • Target • Gen • Enzim • (Panah → menunjukkan arah efek / relasi) • Transporter • Carrier

1. Pendahuluan & Konsep

Fitur visualisasi ini dikembangkan menggunakan pendekatan Graph Theory untuk memetakan hubungan polifarmasi dan molekuler. Entitas (Obat, Target, Gen) direpresentasikan sebagai Simpul (Nodes), sedangkan hubungan biologisnya sebagai Sisi (Edges).

2. Sumber Data (Validasi)

Data Obat: Diekstraksi dari elemen drugbank-id dan name pada skema XML DrugBank.
Target Protein: Diambil dari elemen targets/target yang memuat polipeptida sasaran.
Genetik: Disinkronisasi dari sub-elemen gene-name dan varian snp-effects.
Genetik: Jumlah titik node dibatasi pada maksimal 10 (Slice=10) interaksi untuk menghindari tumpukan data.

3. Algoritma Visualisasi

Tata letak grafik menggunakan algoritma Force-Directed Graph (Barnes-Hut). Model fisika ini menerapkan gaya tolak-menolak antar simpul (Gravitasi: -3000) agar tidak tumpang tindih, serta gaya pegas (Spring: 0.04) pada garis penghubung untuk fleksibilitas interaksi.

4. Legenda Visual

Obat Utama (Pusat Analisis)

Target Protein (Mekanisme)

Gen (Faktor Genetik)

Metode ini mendukung analisis Precision Medicine dan evaluasi risiko Drug-Drug Interaction (DDI).

Profil Farmakokinetik

Waktu Paruh (Half-Life) The half-life of temsavir is approximately 11 hours.[L14867] Fostemsavir is generally undetectable in plasma following oral administration.

Volume Distribusi The steady-state volume of distribution of temsavir following intravenous administration is approximately 29.5 L.[L14867]

Klirens (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.[L14867]

Absorpsi

The absorption of temsavir is significantly limited by suboptimal dissolution and solubility following oral administration.^A215057 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%.^L14867 The C_max and AUC_tau following oral administration of fostemsavir 600mg twice daily was 1770 ng/mL and 12,900 ng.h/L, respectively, with a T_max of approximately 2 hours.^L14867 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%.^L14867

Metabolisme

Fostemsavir is rapidly hydrolyzed to temsavir, its active metabolite, by alkaline phosphatase(s) present at the brush border membrane of the intestinal lumen.^A215057 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.^L14867 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.^L14867 Both temsavir and its two predominant metabolites are known to inhibit BCRP.^L14867

Rute Eliminasi

Temsavir is highly metabolized, after which it is excreted in the urine and feces as inactive metabolites.^L14867 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.^L14867

Interaksi Makanan

2 Data

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

Interaksi Obat

714 Data

Ranolazine	The serum concentration of Fostemsavir can be increased when it is combined with Ranolazine.
Eluxadoline	The serum concentration of Eluxadoline can be increased when it is combined with Fostemsavir.
Leuprolide	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Leuprolide.
Goserelin	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Goserelin.
Erythromycin	The serum concentration of Fostemsavir can be increased when it is combined with Erythromycin.
Azithromycin	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Azithromycin.
Moxifloxacin	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Moxifloxacin.
Sulfisoxazole	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Sulfisoxazole.
Amitriptyline	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Amitriptyline.
Diltiazem	The metabolism of Fostemsavir can be decreased when combined with Diltiazem.
Clozapine	The metabolism of Fostemsavir can be decreased when combined with Clozapine.
Sulpiride	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Sulpiride.
Nimodipine	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Nimodipine.
Promazine	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Promazine.
Prochlorperazine	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Prochlorperazine.
Droperidol	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Droperidol.
Imipramine	The serum concentration of Imipramine can be increased when it is combined with Fostemsavir.
Chlorpromazine	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Chlorpromazine.
Oxaliplatin	Fostemsavir may decrease the excretion rate of Oxaliplatin which could result in a higher serum level.
Ciprofloxacin	The metabolism of Fostemsavir can be decreased when combined with Ciprofloxacin.
Fluorouracil	Fostemsavir may decrease the excretion rate of Fluorouracil which could result in a higher serum level.
Perflutren	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Perflutren.
Cinnarizine	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Cinnarizine.
Atropine	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Atropine.
Chloroquine	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Chloroquine.
Adenosine	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Adenosine.
Pentamidine	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Pentamidine.
Gadobenic acid	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Gadobenic acid.
Carbinoxamine	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Carbinoxamine.
Dolasetron	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Dolasetron.
Roxithromycin	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Roxithromycin.
Nalidixic acid	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Nalidixic acid.
Cinoxacin	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Cinoxacin.
Granisetron	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Granisetron.
Ondansetron	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Ondansetron.
Levosimendan	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Levosimendan.
Mesoridazine	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Mesoridazine.
Desloratadine	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Desloratadine.
Lomefloxacin	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Lomefloxacin.
Dimenhydrinate	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Dimenhydrinate.
Primaquine	The metabolism of Fostemsavir can be decreased when combined with Primaquine.
Papaverine	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Papaverine.
Chlorpheniramine	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Chlorpheniramine.
Nifedipine	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Nifedipine.
Levofloxacin	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Levofloxacin.
Gemifloxacin	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Gemifloxacin.
Ofloxacin	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Ofloxacin.
Propafenone	The serum concentration of Fostemsavir can be increased when it is combined with Propafenone.
Flecainide	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Flecainide.
Quetiapine	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Quetiapine.
Levacetylmethadol	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Levacetylmethadol.
Clomipramine	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Clomipramine.
Mibefradil	The serum concentration of Fostemsavir can be increased when it is combined with Mibefradil.
Probucol	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Probucol.
Aceprometazine	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Aceprometazine.
Terlipressin	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Terlipressin.
Prenylamine	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Prenylamine.
Fluspirilene	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Fluspirilene.
Lofexidine	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Lofexidine.
Azimilide	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Azimilide.
Pracinostat	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Pracinostat.
Technetium Tc-99m ciprofloxacin	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Technetium Tc-99m ciprofloxacin.
Garenoxacin	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Garenoxacin.
Tedisamil	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Tedisamil.
Tucidinostat	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Tucidinostat.
Telavancin	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Telavancin.
Pazopanib	Fostemsavir may decrease the excretion rate of Pazopanib which could result in a higher serum level.
Nemonoxacin	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Nemonoxacin.
Panobinostat	The serum concentration of Panobinostat can be increased when it is combined with Fostemsavir.
Nilvadipine	The metabolism of Fostemsavir can be decreased when combined with Nilvadipine.
Antazoline	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Antazoline.
Crizotinib	The serum concentration of Fostemsavir can be increased when it is combined with Crizotinib.
Bedaquiline	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Bedaquiline.
Fendiline	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Fendiline.
Eperisone	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Eperisone.
Butriptyline	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Butriptyline.
Ceritinib	The serum concentration of Ceritinib can be increased when it is combined with Fostemsavir.
Lenvatinib	Fostemsavir may decrease the excretion rate of Lenvatinib which could result in a higher serum level.
Melperone	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Melperone.
Benidipine	The metabolism of Fostemsavir can be decreased when combined with Benidipine.
Dexchlorpheniramine maleate	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Dexchlorpheniramine maleate.
Delamanid	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Delamanid.
Amifampridine	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Amifampridine.
Encorafenib	The serum concentration of Fostemsavir can be decreased when it is combined with Encorafenib.
Mocetinostat	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Mocetinostat.
Entinostat	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Entinostat.
Gilteritinib	Gilteritinib may decrease the excretion rate of Fostemsavir which could result in a higher serum level.
CUDC-101	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with CUDC-101.
Simendan	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Simendan.
Ricolinostat	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Ricolinostat.
Mizolastine	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Mizolastine.
Abexinostat	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Abexinostat.
Oxatomide	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Oxatomide.
Sitafloxacin	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Sitafloxacin.
Sultopride	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Sultopride.
Otilonium	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Otilonium.
Nizofenone	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Nizofenone.
Bunaftine	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Bunaftine.
Lorcainide	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Lorcainide.
Dexchlorpheniramine	The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Dexchlorpheniramine.

Target Protein

Envelope glycoprotein gp160 env

Referensi & Sumber

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.

Artikel (PubMed)

PMID: 29271653
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.
PMID: 30980734
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.
PMID: 29920093
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.
PMID: 22762019
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.

Link

Contoh Produk & Brand

Produk: 4 • International brands: 0

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Sekuens Gen/Protein (FASTA)

Sekuens dimuat saat dibutuhkan agar halaman tetap ringan.