Peringatan Keamanan

Based on the mechanism of action and findings in animal reproduction studies, erdafitinib can cause fetal harm when administered to a pregnant woman. There are no available data on erdafitinib use in pregnant women to inform a drug-associated risk. Oral administration of erdafitinib to pregnant rats during organogenesis caused malformations and embryo- fetal death at maternal exposures that were less than the human exposures at the maximum recommended human dose based on AUC. Advise pregnant women and females of reproductive potential of the potential risk to the fetus.^L49731

There are no data on the presence of erdafitinib in human milk, or the effects of erdafitinib on the breastfed child, or on milk production. Because of the potential for serious adverse reactions from erdafitinib in a breastfed child, advise lactating women not to breastfeed during treatment with erdafitinib and for one month following the last dose.^L49731

Pregnancy testing is recommended for females of reproductive potential prior to initiating treatment with erdafitinib.^L49731

Erdafitinib can cause fetal harm when administered to a pregnant woman FDA Label. Advise females of reproductive potential to use effective contraception during treatment with erdafitinib and for one month after the last dose.^L49731

Advise male patients with female partners of reproductive potential to use effective contraception during treatment with erdafitinib and for one month after the last dose.^L49731

Based on findings from animal studies, erdafitinib may impair fertility in females of reproductive potential.^L49731

Safety and effectiveness of erdafitinib in pediatric patients have not been established.^L49731

No overall differences in safety or effectiveness were observed between these patients and younger patients in the use of erdafitinib.^L49731

Erdafitinib plasma concentrations were predicted to be higher in patients with the CYP2C9*3/*3 genotype. Monitor for increased adverse reactions in patients who are known or suspected to have CYP2C9*3/*3 genotype.^L49731

Carcinogenicity studies have not been conducted with erdafitinib.^L49731

Erdafitinib was not mutagenic in a bacterial reverse mutation (Ames) assay and was not clastogenic in an in vitro micronucleus or an in vivo rat bone marrow micronucleus assay.^L49731

Fertility studies in animals have not been conducted with erdafitinib. In the 3-month repeat-dose toxicity study, erdafitinib showed effects on female reproductive organs (necrosis of the ovarian corpora lutea) in rats at an exposure less than the human exposure (AUC) at maximum recommended human dose.^L49731

Erdafitinib

DB12147

small molecule approved investigational

Deskripsi

In early April of 2019, the US FDA approved Janssen Pharmaceutical Companies' brand name Balversa (erdafitinib) as the first-ever fibroblast growth factor receptor (FGFR) kinase inhibitor indicated for patients with locally advanced or metastatic urothelial carcinoma, with susceptible FGFR3 or FGFR2 genetic alterations, that has progressed during or following platinum-containing chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy. L5956, L5959 At the same time, the FDA also approved the therascreen FGFR RGQ RT-PCR Kit (Qiagen) for utilization as a companion diagnostic with erdafitinib for selecting patients for the indicated therapy L5956, L5959.

Erdafitinib is the first personalized treatment targeting susceptible FGFR genetic alterations for patients with metastatic bladder cancer, which demonstrates the development of more personalized and precise medicines tailoring to a patient's specific genetic mutation.L5956, L5959 Considering urothelial cancer is statistically the fourth most common kind of cancer in the world, the introduction of erdafitinib offers a much-needed new option in the ever-expanding therapeutic tool kit to treat such a prevalent medical condition.^F4372

Struktur Molekul 2D

Berat 446.555

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 mean effective half-life documented for erdafitinib is 59 hours, although it has also been observed between 50 to 60 hours.[L45648,A177115]

Volume Distribusi The mean apparent volume of distribution determined for erdafitinib is about 26 to 29 L in patients.[A177115,L45648]

Klirens (Clearance) The mean total apparent clearance (CL/F) documented for erdafitinib is about 0.362 L/h, while the oral clearance has been observed to be approximately 0.26 L/h [L45648,A177115].

Absorpsi

Following administration of erdafitinib 8 mg once daily, the mean (coefficient of variation CV%) steady-state maximum observed plasma concentration (C_max), area under the curve (AUC_tau), and minimum observed plasma concentration (C_min) were 1,399 ng/mL (51%), 29,268 ng·h/mL (60%), and 936 ng/mL (65%), respectively.^L45648 Following single and repeated once-daily dosing, erdafitinib exposure (maximum observed plasma concentration C_max and area under the plasma concentration-time curve AUC) increased proportionally across the dose range of 0.5 to 12 mg (0.06 to 1.3 times the maximum approved recommended dose).^L45648 Steady-state was achieved after 2 weeks with once-daily dosing and the mean accumulation ratio was 4-fold.^L45648 The median time to achieve peak plasma concentration (t_max) was 2.5 hours (range: 2 to 6 hours).^L45648 No clinically meaningful differences with erdafitinib pharmacokinetics were observed following the administration of a high-fat and high-calorie meal (800 calories to 1,000 calories with approximately 50% of the total caloric content of the meal from fat) in healthy subjects.^L45648

Metabolisme

Erdafitinib is primarily metabolized by the cytochrome CYP2C9 and CYP3A4 isoenzymes in humans to form the O-demethylated major metabolite.L45648, L45653. The contribution of CYP2C9 and CYP3A4 in the total clearance of erdafitinib is estimated to be 39% and 20% respectively.^L45648 Unchanged erdafitinib was ultimately the predominant drug-related moiety found in the plasma - no circulating metabolites were observed.^L45648

Rute Eliminasi

After administering a single oral dose of radiolabeled erdafitinib, about 69% of the dose was recovered in feces (19% as unchanged) and 19% in urine (13% as unchanged).^L45648

Interaksi Makanan

3 Data

1. Exercise caution with grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which may increase the serum concentration of erdafitinib.
2. Exercise caution with St. John's Wort. This herb induces the CYP3A metabolism of erdafitinib and may reduce its serum concentration.
3. Take with or without food. No clinically meaningful differences with erdafitinib pharmacokinetics were observed following administration of a high-fat and high-calorie meal (800 calories to 1,000 calories with approximately 50% of total caloric content of the meal from fat) in healthy subjects.

Interaksi Obat

868 Data

Armodafinil	The metabolism of Erdafitinib can be increased when combined with Armodafinil.
Bosutinib	The serum concentration of Bosutinib can be increased when it is combined with Erdafitinib.
Colchicine	The serum concentration of Colchicine can be increased when it is combined with Erdafitinib.
Edoxaban	The serum concentration of Edoxaban can be increased when it is combined with Erdafitinib.
Ledipasvir	The serum concentration of Ledipasvir can be increased when it is combined with Erdafitinib.
Naloxegol	The serum concentration of Naloxegol can be increased when it is combined with Erdafitinib.
Pazopanib	The serum concentration of Pazopanib can be increased when it is combined with Erdafitinib.
Prucalopride	The serum concentration of Prucalopride can be increased when it is combined with Erdafitinib.
Ranolazine	The serum concentration of Ranolazine can be increased when it is combined with Erdafitinib.
Silodosin	The excretion of Silodosin can be decreased when combined with Erdafitinib.
Rifaximin	The serum concentration of Rifaximin can be increased when it is combined with Erdafitinib.
Metreleptin	The metabolism of Erdafitinib can be increased when combined with Metreleptin.
Crizotinib	The metabolism of Erdafitinib can be decreased when combined with Crizotinib.
Doxorubicin	The serum concentration of Doxorubicin can be increased when it is combined with Erdafitinib.
Betrixaban	The serum concentration of Betrixaban can be increased when it is combined with Erdafitinib.
Tipiracil	The excretion of Tipiracil can be decreased when combined with Erdafitinib.
Pitolisant	The serum concentration of Erdafitinib can be decreased when it is combined with Pitolisant.
Varenicline	The excretion of Varenicline can be decreased when combined with Erdafitinib.
Solriamfetol	The serum concentration of Solriamfetol can be increased when it is combined with Erdafitinib.
Prazosin	The serum concentration of Prazosin can be increased when it is combined with Erdafitinib.
Ranitidine	The serum concentration of Ranitidine can be increased when it is combined with Erdafitinib.
Choline salicylate	The serum concentration of Choline salicylate can be increased when it is combined with Erdafitinib.
Choline	The serum concentration of Choline can be increased when it is combined with Erdafitinib.
Metformin	The serum concentration of Metformin can be increased when it is combined with Erdafitinib.
Norepinephrine	The serum concentration of Norepinephrine can be increased when it is combined with Erdafitinib.
Reserpine	The serum concentration of Reserpine can be increased when it is combined with Erdafitinib.
Pramipexole	The serum concentration of Pramipexole can be increased when it is combined with Erdafitinib.
Lamivudine	The serum concentration of Lamivudine can be increased when it is combined with Erdafitinib.
Amantadine	The serum concentration of Amantadine can be increased when it is combined with Erdafitinib.
Dopamine	The serum concentration of Dopamine can be increased when it is combined with Erdafitinib.
Memantine	The serum concentration of Memantine can be increased when it is combined with Erdafitinib.
Histamine	The serum concentration of Histamine can be increased when it is combined with Erdafitinib.
Agmatine	The serum concentration of Agmatine can be increased when it is combined with Erdafitinib.
Nafamostat	The serum concentration of Nafamostat can be increased when it is combined with Erdafitinib.
Dabigatran etexilate	The serum concentration of Dabigatran etexilate can be increased when it is combined with Erdafitinib.
Felbamate	The serum concentration of Erdafitinib can be increased when it is combined with Felbamate.
Lesinurad	The metabolism of Erdafitinib can be increased when combined with Lesinurad.
Warfarin	The serum concentration of Warfarin can be increased when it is combined with Erdafitinib.
Oritavancin	The metabolism of Erdafitinib can be increased when combined with Oritavancin.
Esketamine	The metabolism of Erdafitinib can be increased when combined with Esketamine.
Genistein	The metabolism of Erdafitinib can be increased when combined with Genistein.
Asunaprevir	The metabolism of Erdafitinib can be increased when combined with Asunaprevir.
Topiramate	The metabolism of Erdafitinib can be increased when combined with Topiramate.
Rifabutin	The metabolism of Erdafitinib can be increased when combined with Rifabutin.
Rufinamide	The metabolism of Erdafitinib can be increased when combined with Rufinamide.
Glycerol phenylbutyrate	The metabolism of Erdafitinib can be increased when combined with Glycerol phenylbutyrate.
Eslicarbazepine acetate	The metabolism of Erdafitinib can be increased when combined with Eslicarbazepine acetate.
Sarilumab	The metabolism of Erdafitinib can be increased when combined with Sarilumab.
Troglitazone	The serum concentration of Erdafitinib can be increased when it is combined with Troglitazone.
Sulfinpyrazone	The serum concentration of Erdafitinib can be increased when it is combined with Sulfinpyrazone.
Medroxyprogesterone acetate	The metabolism of Erdafitinib can be increased when combined with Medroxyprogesterone acetate.
Phenylbutazone	The metabolism of Erdafitinib can be increased when combined with Phenylbutazone.
Ethanol	The metabolism of Erdafitinib can be increased when combined with Ethanol.
Clevidipine	The metabolism of Erdafitinib can be increased when combined with Clevidipine.
Probenecid	The metabolism of Erdafitinib can be increased when combined with Probenecid.
Cyclophosphamide	The serum concentration of Cyclophosphamide can be increased when it is combined with Erdafitinib.
Rofecoxib	The metabolism of Erdafitinib can be increased when combined with Rofecoxib.
Terbinafine	The metabolism of Erdafitinib can be increased when combined with Terbinafine.
Thiamylal	The metabolism of Erdafitinib can be increased when combined with Thiamylal.
Ifosfamide	The serum concentration of Ifosfamide can be increased when it is combined with Erdafitinib.
Seratrodast	The metabolism of Erdafitinib can be increased when combined with Seratrodast.
Mifepristone	The serum concentration of Erdafitinib can be increased when it is combined with Mifepristone.
Cerivastatin	The metabolism of Erdafitinib can be increased when combined with Cerivastatin.
Tamoxifen	The serum concentration of Tamoxifen can be increased when it is combined with Erdafitinib.
Clozapine	The metabolism of Erdafitinib can be increased when combined with Clozapine.
Testosterone	The metabolism of Erdafitinib can be increased when combined with Testosterone.
Estradiol acetate	The metabolism of Erdafitinib can be increased when combined with Estradiol acetate.
Estradiol benzoate	The metabolism of Erdafitinib can be increased when combined with Estradiol benzoate.
Estradiol cypionate	The metabolism of Erdafitinib can be increased when combined with Estradiol cypionate.
Estradiol dienanthate	The metabolism of Erdafitinib can be increased when combined with Estradiol dienanthate.
Estradiol valerate	The metabolism of Erdafitinib can be increased when combined with Estradiol valerate.
Acetaminophen	The metabolism of Erdafitinib can be increased when combined with Acetaminophen.
Vitamin E	The metabolism of Erdafitinib can be increased when combined with Vitamin E.
Flunisolide	The metabolism of Erdafitinib can be increased when combined with Flunisolide.
Butalbital	The metabolism of Erdafitinib can be increased when combined with Butalbital.
Flucloxacillin	The metabolism of Erdafitinib can be increased when combined with Flucloxacillin.
Aminoglutethimide	The metabolism of Erdafitinib can be increased when combined with Aminoglutethimide.
Beclomethasone dipropionate	The metabolism of Erdafitinib can be increased when combined with Beclomethasone dipropionate.
Griseofulvin	The metabolism of Erdafitinib can be increased when combined with Griseofulvin.
Secobarbital	The metabolism of Erdafitinib can be increased when combined with Secobarbital.
Betamethasone	The metabolism of Erdafitinib can be increased when combined with Betamethasone.
Chlorpromazine	The metabolism of Erdafitinib can be increased when combined with Chlorpromazine.
Dicloxacillin	The metabolism of Erdafitinib can be increased when combined with Dicloxacillin.
Fluocinolone acetonide	The metabolism of Erdafitinib can be increased when combined with Fluocinolone acetonide.
Triamcinolone	The metabolism of Erdafitinib can be increased when combined with Triamcinolone.
Clofibrate	The metabolism of Erdafitinib can be increased when combined with Clofibrate.
Hydrocortisone	The metabolism of Erdafitinib can be increased when combined with Hydrocortisone.
Hydrocortamate	The metabolism of Erdafitinib can be increased when combined with Hydrocortamate.
Oxcarbazepine	The metabolism of Erdafitinib can be increased when combined with Oxcarbazepine.
Methylphenobarbital	The metabolism of Erdafitinib can be increased when combined with Methylphenobarbital.
Prednisolone	The metabolism of Erdafitinib can be increased when combined with Prednisolone.
Norgestimate	The metabolism of Erdafitinib can be increased when combined with Norgestimate.
Methylprednisolone	The metabolism of Erdafitinib can be increased when combined with Methylprednisolone.
Metyrapone	The metabolism of Erdafitinib can be increased when combined with Metyrapone.
Rifapentine	The metabolism of Erdafitinib can be increased when combined with Rifapentine.
Budesonide	The metabolism of Erdafitinib can be increased when combined with Budesonide.
Paclitaxel	The serum concentration of Paclitaxel can be increased when it is combined with Erdafitinib.
Corticotropin	The metabolism of Erdafitinib can be increased when combined with Corticotropin.
Cefradine	The metabolism of Erdafitinib can be increased when combined with Cefradine.
Amobarbital	The metabolism of Erdafitinib can be increased when combined with Amobarbital.

Target Protein

Fibroblast growth factor receptor 1 FGFR1

Fibroblast growth factor receptor 2 FGFR2

Fibroblast growth factor receptor 3 FGFR3

Fibroblast growth factor receptor 4 FGFR4

Proto-oncogene tyrosine-protein kinase receptor Ret RET

Macrophage colony-stimulating factor 1 receptor CSF1R

Platelet-derived growth factor receptor alpha PDGFRA

Platelet-derived growth factor receptor beta PDGFRB

Mast/stem cell growth factor receptor Kit KIT

Vascular endothelial growth factor receptor 2 KDR

Referensi & Sumber

Artikel (PubMed)

PMID: 28965185
Nishina T, Takahashi S, Iwasawa R, Noguchi H, Aoki M, Doi T: Safety, pharmacokinetic, and pharmacodynamics of erdafitinib, a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, in patients with advanced or refractory solid tumors. Invest New Drugs. 2018 Jun;36(3):424-434. doi: 10.1007/s10637-017-0514-4. Epub 2017 Sep 30.
PMID: 28341788
Perera TPS, Jovcheva E, Mevellec L, Vialard J, De Lange D, Verhulst T, Paulussen C, Van De Ven K, King P, Freyne E, Rees DC, Squires M, Saxty G, Page M, Murray CW, Gilissen R, Ward G, Thompson NT, Newell DR, Cheng N, Xie L, Yang J, Platero SJ, Karkera JD, Moy C, Angibaud P, Laquerre S, Lorenzi MV: Discovery and Pharmacological Characterization of JNJ-42756493 (Erdafitinib), a Functionally Selective Small-Molecule FGFR Family Inhibitor. Mol Cancer Ther. 2017 Jun;16(6):1010-1020. doi: 10.1158/1535-7163.MCT-16-0589. Epub 2017 Mar 24.
PMID: 26324363
Tabernero J, Bahleda R, Dienstmann R, Infante JR, Mita A, Italiano A, Calvo E, Moreno V, Adamo B, Gazzah A, Zhong B, Platero SJ, Smit JW, Stuyckens K, Chatterjee-Kishore M, Rodon J, Peddareddigari V, Luo FR, Soria JC: Phase I Dose-Escalation Study of JNJ-42756493, an Oral Pan-Fibroblast Growth Factor Receptor Inhibitor, in Patients With Advanced Solid Tumors. J Clin Oncol. 2015 Oct 20;33(30):3401-8. doi: 10.1200/JCO.2014.60.7341. Epub 2015 Aug 31.

Link

Attachment

Contoh Produk & Brand

Produk: 7 • International brands: 0

Produk

Balversa

Tablet, film coated • 3 mg/1 • Oral • US • Approved
Balversa

Tablet, film coated • 4 mg/1 • Oral • US • Approved
Balversa

Tablet, film coated • 5 mg/1 • Oral • US • Approved
Balversa

Tablet • 3 mg • Oral • Canada • Approved
Balversa

Tablet • 4 mg • Oral • Canada • Approved
Balversa

Tablet • 5 mg • Oral • Canada • Approved
Balversa

Tablet • 4 mg • Oral • Canada • Approved

Sekuens Gen/Protein (FASTA)

Sekuens dimuat saat dibutuhkan agar halaman tetap ringan.