Peringatan Keamanan

Most common adverse reactions (?3%) for AKYNZEO capsules are headache, asthenia, dyspepsia, fatigue, constipation and erythema ^L2635.

The safety profile of Akynzeo for injection is generally similar to that seen with Aynzeo capsules ^{FDA label}, ^L2635.

Currently a repeated dose safety study is ongoing in patients receiving anthracycline plus cyclophosphamide to further establish the safety profile in this setting ^L2631.

Fosnetupitant

DB14019

small molecule approved

Deskripsi

In April 2018, the U.S. Food and Drug Administration (FDA) and the Swiss company Helsinn approved the intravenous formulation of AKYNZEO® (NEPA, a fixed antiemetic combination of fosnetupitant, 235mg, and palonosetron, 0.25mg) as an alternative treatment option for patients experiencing chemotherapy-induced nausea and vomiting ^L2631. Fosnetupitant is the pro-drug form of netupitant ^{FDA label}.

Generally, 25% to 30% of patients with a diagnosis of cancer receive chemotherapy as a treatment modality and 70% to 80% of these patients undergoing chemotherapy treatment may experience nausea and vomiting as major side effects. Considered one of the most distressing side effects of chemotherapy, nausea and vomiting has an immense impact on the quality of life of patients receiving certain antineoplastic therapies ^A32865.

Struktur Molekul 2D

Berat 688.608

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) Netupitant is eliminated from the body in a multi-exponential fashion, with an apparent elimination half-life in cancer patients of 80 ± 29 hours (mean ± SD) [FDA label].

Volume Distribusi The mean SD volume of distribution of fosnetupitant in healthy subjects and in patients was 124 +/- 76 L and 296 +/- 535 L, respectively [FDA label].

Klirens (Clearance) Netupitant has a mean estimated systemic clearance of 0.3 ± 9.2 L/h (mean ± SD) after a single oral dose of Akynzeo [FDA label].

Absorpsi

Following single intravenous doses of Akynzeo for injection in patients (235 mg fosnetupitant and 0.25 mg palonosetron infused in 30 minutes) or fosnetupitant in healthy subjects (235 mg fosnetupitant infused in 30 minutes), maximum concentration of fosnetupitant was achieved at the end of the 30-minute infusion ^{FDA label}. Oral bioavailability in each species varied substantially between animals, with 42-105%, 34-83% and 37-62% in rats, dogs, and monkeys. The large variation is most likely due to the low numbers of animals used in the studies ^F29.

Metabolisme

Fosnetupitant is the prodrug of netupitant ^{FDA label}. Netupitant is a moderate inhibitor and substrate of CYP3A4 ^{FDA label}. Akynzeo should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4 systems. One dose of netupitant 300 mg significantly inhibits CYP3A4 for about 6 days. It is avisable to avoid concomitant use of drugs that are CYP3A4 substrates for one week. If not possible, consider dose reduction of CYP3A4 substrates ^{FDA label}. In the human, rat, dog, minipig and marmoset liver microsomal incubations, two major metabolites, an N-demethylation product (M1) and an N-oxidation product (M2), in addition to hydroxylation products (M3), were identified in all species. CYP3A4 was found to be responsible for the oxidation of netupitant to the same metabolites observed also in the incubations with human liver microsomes. Metabolism was extensive, with the metabolites generally achieving greater concentrations than parent drug witin 24 hours. M1 and M2 exposure was similar in rat to humans, but higher in dogs, however M3 was lower in both species than in humans ^F29.

Rute Eliminasi

After one oral dose of 14Cnetupitant, approximately one-half of the administered radioactivity was measured in the urine and feces within 120 hours of the dose. The total of 3.95% and 70.7% of the radioactive dose was measured in the urine and feces collected over 336 hours, respectively, and the average fraction of an oral dose of netupitant excreted unchanged in urine is under 1%, implying that renal clearance is not a significant route of elimination for the netupitant-related entities ^{FDA label}. About 86.5% and 4.7% of administered radioactivity was estimated to be excreted via the feces and urine within 30 days post-dose ^{FDA label}.

Interaksi Makanan

1 Data

1. Avoid St. John's Wort. This herb induces CYP3A metabolism and may reduce serum levels of fosnetupitant.

Interaksi Obat

793 Data

Brexpiprazole	The metabolism of Brexpiprazole can be decreased when combined with Fosnetupitant.
Eliglustat	The metabolism of Eliglustat can be decreased when combined with Fosnetupitant.
Everolimus	The metabolism of Everolimus can be decreased when combined with Fosnetupitant.
Flibanserin	The metabolism of Flibanserin can be decreased when combined with Fosnetupitant.
Ibrutinib	The metabolism of Ibrutinib can be decreased when combined with Fosnetupitant.
Ivabradine	The metabolism of Ivabradine can be decreased when combined with Fosnetupitant.
Ivacaftor	The metabolism of Ivacaftor can be decreased when combined with Fosnetupitant.
Lurasidone	The metabolism of Lurasidone can be decreased when combined with Fosnetupitant.
Naloxegol	The metabolism of Naloxegol can be decreased when combined with Fosnetupitant.
Olaparib	The metabolism of Olaparib can be decreased when combined with Fosnetupitant.
Ranolazine	The metabolism of Ranolazine can be decreased when combined with Fosnetupitant.
Sonidegib	The metabolism of Sonidegib can be decreased when combined with Fosnetupitant.
Avanafil	The metabolism of Avanafil can be decreased when combined with Fosnetupitant.
Eplerenone	The metabolism of Eplerenone can be decreased when combined with Fosnetupitant.
Cilostazol	The metabolism of Cilostazol can be decreased when combined with Fosnetupitant.
Colchicine	The metabolism of Colchicine can be decreased when combined with Fosnetupitant.
Fentanyl	The metabolism of Fentanyl can be decreased when combined with Fosnetupitant.
Iloperidone	The metabolism of Iloperidone can be decreased when combined with Fosnetupitant.
Retapamulin	The metabolism of Retapamulin can be decreased when combined with Fosnetupitant.
Tofacitinib	The metabolism of Tofacitinib can be decreased when combined with Fosnetupitant.
Vardenafil	The metabolism of Vardenafil can be decreased when combined with Fosnetupitant.
Eszopiclone	The metabolism of Eszopiclone can be decreased when combined with Fosnetupitant.
Zopiclone	The metabolism of Zopiclone can be decreased when combined with Fosnetupitant.
Lovastatin	The metabolism of Lovastatin can be decreased when combined with Fosnetupitant.
Alfuzosin	The metabolism of Alfuzosin can be decreased when combined with Fosnetupitant.
Alprazolam	The metabolism of Alprazolam can be decreased when combined with Fosnetupitant.
Warfarin	The serum concentration of Warfarin can be increased when it is combined with Fosnetupitant.
Acenocoumarol	The serum concentration of Acenocoumarol can be increased when it is combined with Fosnetupitant.
(R)-warfarin	The serum concentration of (R)-warfarin can be increased when it is combined with Fosnetupitant.
R,S-Warfarin alcohol	The serum concentration of R,S-Warfarin alcohol can be increased when it is combined with Fosnetupitant.
S,R-Warfarin alcohol	The serum concentration of S,R-Warfarin alcohol can be increased when it is combined with Fosnetupitant.
(S)-Warfarin	The serum concentration of (S)-Warfarin can be increased when it is combined with Fosnetupitant.
Midazolam	The serum concentration of Midazolam can be increased when it is combined with Fosnetupitant.
Tacrolimus	The serum concentration of Tacrolimus can be increased when it is combined with Fosnetupitant.
Atorvastatin	The metabolism of Atorvastatin can be decreased when combined with Fosnetupitant.
Dexamethasone	The metabolism of Dexamethasone can be decreased when combined with Fosnetupitant.
Cobimetinib	The metabolism of Cobimetinib can be decreased when combined with Fosnetupitant.
Pitolisant	The serum concentration of Fosnetupitant can be decreased when it is combined with Pitolisant.
Aripiprazole	The metabolism of Aripiprazole can be decreased when combined with Fosnetupitant.
Aripiprazole lauroxil	The metabolism of Aripiprazole lauroxil can be decreased when combined with Fosnetupitant.
Metreleptin	The metabolism of Fosnetupitant can be increased when combined with Metreleptin.
Tezacaftor	The metabolism of Tezacaftor can be decreased when combined with Fosnetupitant.
Ceritinib	The metabolism of Ceritinib can be decreased when combined with Fosnetupitant.
Dacomitinib	The metabolism of Dacomitinib can be decreased when combined with Fosnetupitant.
Alpelisib	The metabolism of Alpelisib can be decreased when combined with Fosnetupitant.
Idelalisib	The metabolism of Idelalisib can be decreased when combined with Fosnetupitant.
Osimertinib	The metabolism of Osimertinib can be decreased when combined with Fosnetupitant.
Pimozide	The metabolism of Pimozide can be decreased when combined with Fosnetupitant.
Fosphenytoin	The metabolism of Fosphenytoin can be decreased when combined with Fosnetupitant.
Cyclosporine	The metabolism of Cyclosporine can be decreased when combined with Fosnetupitant.
Dofetilide	The metabolism of Dofetilide can be decreased when combined with Fosnetupitant.
Theophylline	The metabolism of Theophylline can be decreased when combined with Fosnetupitant.
Carbamazepine	The metabolism of Carbamazepine can be decreased when combined with Fosnetupitant.
Sirolimus	The metabolism of Sirolimus can be decreased when combined with Fosnetupitant.
Quinidine	The metabolism of Quinidine can be decreased when combined with Fosnetupitant.
Phenprocoumon	The metabolism of Phenprocoumon can be decreased when combined with Fosnetupitant.
Busulfan	The metabolism of Busulfan can be decreased when combined with Fosnetupitant.
Aminophylline	The metabolism of Aminophylline can be decreased when combined with Fosnetupitant.
Paclitaxel	The metabolism of Paclitaxel can be decreased when combined with Fosnetupitant.
Dasatinib	The metabolism of Dasatinib can be decreased when combined with Fosnetupitant.
Digitoxin	The metabolism of Digitoxin can be decreased when combined with Fosnetupitant.
Dronedarone	The metabolism of Dronedarone can be decreased when combined with Fosnetupitant.
Temsirolimus	The metabolism of Temsirolimus can be decreased when combined with Fosnetupitant.
Tianeptine	The metabolism of Tianeptine can be decreased when combined with Fosnetupitant.
Astemizole	The metabolism of Astemizole can be decreased when combined with Fosnetupitant.
Lomitapide	The metabolism of Lomitapide can be decreased when combined with Fosnetupitant.
Methotrexate	The metabolism of Methotrexate can be decreased when combined with Fosnetupitant.
Vinorelbine	The metabolism of Vinorelbine can be decreased when combined with Fosnetupitant.
Vincristine	The metabolism of Vincristine can be decreased when combined with Fosnetupitant.
Vinblastine	The metabolism of Vinblastine can be decreased when combined with Fosnetupitant.
Doxorubicin	The serum concentration of Doxorubicin can be increased when it is combined with Fosnetupitant.
Docetaxel	The metabolism of Docetaxel can be decreased when combined with Fosnetupitant.
Thiotepa	The metabolism of Thiotepa can be decreased when combined with Fosnetupitant.
Trabectedin	The metabolism of Trabectedin can be decreased when combined with Fosnetupitant.
Vandetanib	The metabolism of Vandetanib can be decreased when combined with Fosnetupitant.
Vemurafenib	The metabolism of Vemurafenib can be decreased when combined with Fosnetupitant.
Alectinib	The metabolism of Alectinib can be decreased when combined with Fosnetupitant.
Venetoclax	The metabolism of Venetoclax can be decreased when combined with Fosnetupitant.
Vinflunine	The metabolism of Vinflunine can be decreased when combined with Fosnetupitant.
Acalabrutinib	The metabolism of Acalabrutinib can be decreased when combined with Fosnetupitant.
Enasidenib	The metabolism of Enasidenib can be decreased when combined with Fosnetupitant.
Bortezomib	The metabolism of Bortezomib can be decreased when combined with Fosnetupitant.
Cabergoline	The metabolism of Cabergoline can be decreased when combined with Fosnetupitant.
Vindesine	The metabolism of Vindesine can be decreased when combined with Fosnetupitant.
Sorafenib	The metabolism of Sorafenib can be decreased when combined with Fosnetupitant.
Teniposide	The metabolism of Teniposide can be decreased when combined with Fosnetupitant.
Erlotinib	The metabolism of Erlotinib can be decreased when combined with Fosnetupitant.
Tamoxifen	The metabolism of Tamoxifen can be decreased when combined with Fosnetupitant.
Etoposide	The metabolism of Etoposide can be decreased when combined with Fosnetupitant.
Ifosfamide	The metabolism of Ifosfamide can be decreased when combined with Fosnetupitant.
Sunitinib	The metabolism of Sunitinib can be decreased when combined with Fosnetupitant.
Ixabepilone	The metabolism of Ixabepilone can be decreased when combined with Fosnetupitant.
Pazopanib	The metabolism of Pazopanib can be decreased when combined with Fosnetupitant.
Panobinostat	The metabolism of Panobinostat can be decreased when combined with Fosnetupitant.
Bosutinib	The metabolism of Bosutinib can be decreased when combined with Fosnetupitant.
Axitinib	The metabolism of Axitinib can be decreased when combined with Fosnetupitant.
Crizotinib	The metabolism of Crizotinib can be decreased when combined with Fosnetupitant.
Brentuximab vedotin	The metabolism of Brentuximab vedotin can be decreased when combined with Fosnetupitant.
Ruxolitinib	The metabolism of Ruxolitinib can be decreased when combined with Fosnetupitant.
Ponatinib	The metabolism of Ponatinib can be decreased when combined with Fosnetupitant.

Target Protein

Substance-P receptor TACR1

Referensi & Sumber

Artikel (PubMed)

PMID: 27713845
Coyne JW: The First Oral Fixed-Dose Combination of Netupitant and Palonosetron for the Treatment of Chemotherapy-Induced Nausea and Vomiting. J Adv Pract Oncol. 2016 Jan-Feb;7(1):66-70. Epub 2016 Jan 1.
PMID: 25552904
Navari RM: Profile of netupitant/palonosetron (NEPA) fixed dose combination and its potential in the treatment of chemotherapy-induced nausea and vomiting (CINV). Drug Des Devel Ther. 2014 Dec 17;9:155-61. doi: 10.2147/DDDT.S76158. eCollection 2015.

Link

Attachment

EMA label

Contoh Produk & Brand

Produk: 3 • International brands: 0

Produk

Akynzeo

Injection • - • Intravenous • US • Approved
Akynzeo

Injection • - • Intravenous • US • Approved
Akynzeo

Injection • - • Intravenous • US • Approved

Sekuens Gen/Protein (FASTA)

Sekuens dimuat saat dibutuhkan agar halaman tetap ringan.