Peringatan Keamanan

Toxicity information regarding zavegepant is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as serious hypersensitivity reaction occurs.^L45505 Symptomatic and supportive measures are recommended. The intranasal administration of zavegepant to transgenic mice carrying c-Ha-ras oncogenes (Tg-rasH2) at a maximum concentration of 2.5 mg/day up to 26 weeks did not lead to the development of drug-related tumors. The same results were obtained when rats were given up to 18.8 mg/kg/day of intranasal zavegepant for up to 96 weeks, reaching a plasma exposure 140 times the one in humans receiving the maximum recommended human dose (MRHD). In in vitro and in vivo mutagenesis assays, zavegepant showed negative results. Male and female rats given up to 25 mg/kg/day of zavegepant subcutaneously before and during mating and up to gestation day 7 in females did not present adverse effects on fertility or reproductive performance. Plasma exposure was equivalent to 2800 times the one in humans given the MRHD.^L45505

Zavegepant

DB15688

small molecule approved investigational

Deskripsi

Zavegepant (BHV-3500) is a calcitonin gene-related peptide (CGRP) receptor antagonist.^L45505 CGRP is released from sensory nerves and acts as a strong vasodilator, and thanks to these properties, it is involved in pain pathways. CGRP receptors are expressed in the central and peripheral nervous system; however, CGRP does not cross the blood-brain barrier, suggesting that it acts on peripheral nerves. In migraine, CGRP innervates pain-producing meningeal blood vessels and is released by trigeminal nerve stimulation. Since they inhibit these mechanisms and desensitize neuronal circuits, the use of CGRP receptor antagonists is beneficial in the treatment of migraine.^A258195

Small molecule CGRP antagonists are also known as "gepants", and this category includes other drugs such as rimegepant and ubrogepant. Zavegepant is a third-generation CGRP receptor antagonist that is small in size and highly soluble. Due to its pharmacological properties, it can be administered intranasally.A258190,A258195 In March 2023, the FDA approved the use of zavegepant nasal spray for the acute treatment of migraine with or without aura in adults.L45505,L45510 A clinical trial (NCT04804033) is currently investigating the efficacy and safety of oral zavegepant in migraine prevention, and another one (NCT04987944) is evaluating the safety and efficacy of oral zavegepant (150 mg bid) in subjects with mild allergic asthma.^A258200

Struktur Molekul 2D

Berat 638.817

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) Following a 10 mg dose, intranasal zavegepant has an effective half-life of 6.55 hours.[L45505]

Volume Distribusi Intranasal zavegepant has a mean apparent volume of distribution of approximately 1774 L.[L45505]

Klirens (Clearance) Intranasal zavegepant has a mean apparent clearance of 266 L/h.[L45505]

Absorpsi

After a single intranasal dose of zavegepant (10 mg), the peak plasma concentration was detected approximately 30 minutes later. The absolute bioavailability of zavegepant administered with a nasal spray is approximately 5%. Up to 40 mg (4 times the recommended dose of 10 mg), a single intranasal dose of zavegepant has slightly less than dose-proportional pharmacokinetics. There was no evidence of zavegepant accumulation with once-a-day zavegepant taken for 14 days.^L45505 Compared to normal subjects, patients with moderate hepatic impairment (Child-Pugh B) have a C_max and AUC 16% and 1.9-fold higher, respectively; however, these changes are not expected to be clinically significant based on clinical safety experience and minimal accumulation of drug exposures. In subjects with estimated creatinine clearance (CLcr) greater or equal to 30 mL/min, the differences in zavegepant pharmacokinetics are not expected to be clinically significant. In patients with a CLcr from 15 to 29 mL/min, zavegepant exposure may increase.^L45505

Metabolisme

In vitro, zavegepant is mainly metabolized by CYP3A4, and by CYP2D6 to a lesser extent. After a single intravenous dose of 14C-zavegepant (5 mg), approximately 90% of the circulating dose was unchanged zavegepant. None of the zavegepant metabolites detected in plasma were found at a proportion higher than 10% (no major metabolites).^L45505

Rute Eliminasi

Zavegepant is mainly excreted via the biliary/fecal route, while the renal route plays a minor role in its elimination. In healthy male subjects given a single dose of 5 mg 14C-zavegepant intravenously, approximately 80% and 11% of the dose were recovered as unchanged zavegepant in feces and urine, respectively.^L45505

Interaksi Obat

68 Data

Progesterone	The serum concentration of Zavegepant can be decreased when it is combined with Progesterone.
Cyclosporine	The serum concentration of Zavegepant can be increased when it is combined with Cyclosporine.
Erythromycin	The serum concentration of Zavegepant can be increased when it is combined with Erythromycin.
Nelfinavir	The serum concentration of Zavegepant can be increased when it is combined with Nelfinavir.
Beclomethasone dipropionate	The serum concentration of Zavegepant can be increased when it is combined with Beclomethasone dipropionate.
Ritonavir	The serum concentration of Zavegepant can be increased when it is combined with Ritonavir.
Vincristine	The serum concentration of Zavegepant can be increased when it is combined with Vincristine.
Ivermectin	The serum concentration of Zavegepant can be increased when it is combined with Ivermectin.
Nystatin	The serum concentration of Zavegepant can be increased when it is combined with Nystatin.
Roxithromycin	The serum concentration of Zavegepant can be increased when it is combined with Roxithromycin.
Sulfasalazine	The serum concentration of Zavegepant can be increased when it is combined with Sulfasalazine.
Mifepristone	The serum concentration of Zavegepant can be increased when it is combined with Mifepristone.
Tipranavir	The serum concentration of Zavegepant can be increased when it is combined with Tipranavir.
Dipyridamole	The serum concentration of Zavegepant can be increased when it is combined with Dipyridamole.
Telithromycin	The serum concentration of Zavegepant can be increased when it is combined with Telithromycin.
Novobiocin	The serum concentration of Zavegepant can be increased when it is combined with Novobiocin.
Atazanavir	The serum concentration of Zavegepant can be increased when it is combined with Atazanavir.
Nefazodone	The serum concentration of Zavegepant can be increased when it is combined with Nefazodone.
Clarithromycin	The serum concentration of Zavegepant can be increased when it is combined with Clarithromycin.
Gemfibrozil	The serum concentration of Zavegepant can be increased when it is combined with Gemfibrozil.
Everolimus	The serum concentration of Zavegepant can be increased when it is combined with Everolimus.
Lopinavir	The serum concentration of Zavegepant can be increased when it is combined with Lopinavir.
Dronedarone	The serum concentration of Zavegepant can be increased when it is combined with Dronedarone.
Ataluren	The serum concentration of Zavegepant can be increased when it is combined with Ataluren.
Cobimetinib	The serum concentration of Zavegepant can be increased when it is combined with Cobimetinib.
Dovitinib	The serum concentration of Zavegepant can be increased when it is combined with Dovitinib.
Simeprevir	The serum concentration of Zavegepant can be increased when it is combined with Simeprevir.
Ginsenoside Rb1	The serum concentration of Zavegepant can be increased when it is combined with Ginsenoside Rb1.
Rilpivirine	The serum concentration of Zavegepant can be increased when it is combined with Rilpivirine.
Dabrafenib	The serum concentration of Zavegepant can be increased when it is combined with Dabrafenib.
Idelalisib	The serum concentration of Zavegepant can be increased when it is combined with Idelalisib.
Cobicistat	The serum concentration of Zavegepant can be increased when it is combined with Cobicistat.
Daclatasvir	The serum concentration of Zavegepant can be increased when it is combined with Daclatasvir.
Sacubitril	The serum concentration of Zavegepant can be increased when it is combined with Sacubitril.
Paritaprevir	The serum concentration of Zavegepant can be increased when it is combined with Paritaprevir.
Silibinin	The serum concentration of Zavegepant can be increased when it is combined with Silibinin.
Asunaprevir	The serum concentration of Zavegepant can be increased when it is combined with Asunaprevir.
Velpatasvir	The serum concentration of Zavegepant can be increased when it is combined with Velpatasvir.
Istradefylline	The serum concentration of Zavegepant can be increased when it is combined with Istradefylline.
Fostemsavir	The serum concentration of Zavegepant can be increased when it is combined with Fostemsavir.
Valspodar	The serum concentration of Zavegepant can be increased when it is combined with Valspodar.
Bempedoic acid	The serum concentration of Zavegepant can be increased when it is combined with Bempedoic acid.
Selinexor	The serum concentration of Zavegepant can be increased when it is combined with Selinexor.
Voxilaprevir	The serum concentration of Zavegepant can be increased when it is combined with Voxilaprevir.
Fedratinib	The serum concentration of Zavegepant can be increased when it is combined with Fedratinib.
Darolutamide	The serum concentration of Zavegepant can be increased when it is combined with Darolutamide.
Pexidartinib	The serum concentration of Zavegepant can be increased when it is combined with Pexidartinib.
Enasidenib	The serum concentration of Zavegepant can be increased when it is combined with Enasidenib.
Pibrentasvir	The serum concentration of Zavegepant can be increased when it is combined with Pibrentasvir.
Glecaprevir	The serum concentration of Zavegepant can be increased when it is combined with Glecaprevir.
Remdesivir	The serum concentration of Zavegepant can be increased when it is combined with Remdesivir.
Elexacaftor	The serum concentration of Zavegepant can be increased when it is combined with Elexacaftor.
Pralsetinib	The serum concentration of Zavegepant can be increased when it is combined with Pralsetinib.
Oxymetazoline	The absorption of Zavegepant can be decreased when combined with Oxymetazoline.
Pretomanid	The serum concentration of Zavegepant can be increased when it is combined with Pretomanid.
Rosiglitazone	The serum concentration of Zavegepant can be increased when it is combined with Rosiglitazone.
Zafirlukast	The serum concentration of Zavegepant can be increased when it is combined with Zafirlukast.
Tiratricol	The serum concentration of Zavegepant can be increased when it is combined with Tiratricol.
Estrone sulfate	The serum concentration of Zavegepant can be increased when it is combined with Estrone sulfate.
Sulfobromophthalein	The serum concentration of Zavegepant can be increased when it is combined with Sulfobromophthalein.
Trofinetide	The serum concentration of Zavegepant can be increased when it is combined with Trofinetide.
Leniolisib	The serum concentration of Zavegepant can be increased when it is combined with Leniolisib.
Letermovir	The serum concentration of Zavegepant can be increased when it is combined with Letermovir.
Encorafenib	The serum concentration of Zavegepant can be increased when it is combined with Encorafenib.
Capivasertib	The serum concentration of Zavegepant can be increased when it is combined with Capivasertib.
Ceftobiprole medocaril	The serum concentration of Zavegepant can be increased when it is combined with Ceftobiprole medocaril.
Ceftobiprole	The serum concentration of Zavegepant can be increased when it is combined with Ceftobiprole.
Imetelstat	The serum concentration of Zavegepant can be increased when it is combined with Imetelstat.

Target Protein

Calcitonin gene-related peptide type 1 receptor CALCRL

Referensi & Sumber

Synthesis reference: Coric, V., et al. (2022). Intranasal pharmaceutical compositions of CGRP inhibitors (U.S. Patent No. 2022/0401439 A1). U.S. Patent and Trademark Office. https://patentimages.storage.googleapis.com/52/df/a1/7382d960813673/US20220401439A1.pdf

Artikel (PubMed)

PMID: 36552072
Rissardo JP, Caprara ALF: Gepants for Acute and Preventive Migraine Treatment: A Narrative Review. Brain Sci. 2022 Nov 24;12(12):1612. doi: 10.3390/brainsci12121612.
PMID: 35774914
Noor N, Angelette A, Lawson A, Patel A, Urits I, Viswanath O, Yazdi C, Kaye AD: A Comprehensive Review of Zavegepant as Abortive Treatment for Migraine. Health Psychol Res. 2022 Jun 28;10(3):35506. doi: 10.52965/001c.35506. eCollection 2022.
PMID: 35650458
Altamura C, Brunelli N, Marcosano M, Fofi L, Vernieri F: Gepants - a long way to cure: a narrative review. Neurol Sci. 2022 Sep;43(9):5697-5708. doi: 10.1007/s10072-022-06184-8. Epub 2022 Jun 2.
PMID: 30475090
Martelletti P, Giamberardino MA: Advances in orally administered pharmacotherapy for the treatment of migraine. Expert Opin Pharmacother. 2019 Feb;20(2):209-218. doi: 10.1080/14656566.2018.1549223. Epub 2018 Nov 26.

Link

Contoh Produk & Brand

Produk: 2 • International brands: 1

Produk

Zavzpret

Spray • 10 mg/0.1mL • Nasal • US • Approved
Zavzpret

Spray • 10 mg/0.1mL • Nasal • US • Approved

International Brands

Zavzpret — Pfizer

Sekuens Gen/Protein (FASTA)

Sekuens dimuat saat dibutuhkan agar halaman tetap ringan.