Peringatan Keamanan

Based on literature reports in humans with congenital mutations leading to changes in TRK signaling, findings from animal studies, and its mechanism of action, repotrectinib can cause fetal harm when administered to a pregnant woman. There are no available data on repotrectinib use in pregnant women. Oral administration of repotrectinib to pregnant rats during the period of organogenesis resulted in fetal malformations at doses approximately 0.3 times the recommended dose of 160 mg twice daily based on BSA. Advise pregnant women of the potential risk to a fetus.^L48711

Carcinogenicity studies with repotrectinib were not conducted. Repotrectinib was genotoxic in an in vitro assay in human lymphoblastoid TK6 cells and in an in vivo rat bone marrow micronucleus assay via an aneugenic mechanism of action. Repotrectinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay.^L48711

Dedicated fertility studies were not conducted with repotrectinib. There were no effects on male and female reproductive organs observed in general repeat-dose toxicology studies of up to 3 months in duration in rats and monkeys at any dose level tested, which equated to exposures of up to approximately 3 times the human exposure at the 160 mg twice daily dose based on AUC.^L48711

Repotrectinib

DB16826

small molecule approved investigational

Deskripsi

Repotrectinib is a next-generation tyrosine kinase inhibitor (TKI) specifically designed to address resistance in the treatment of non-small cell lung cancer (NSCLC), specifically due to mutations in the ROS1 gene.^A262056 ROS1 mutations are one of the defined oncogenic drives of NSCLC, and the solvent-front mutation ROS1 G2032R is responsible for 50 to 60% of crizotinib-resistant cases.^A262056 Repotrectinib possesses a compact macrocyclic structure that both limits adverse interactions with resistance mutation hotspots and targets mutations in the solvent-front region.^A262061 Although resistance to multiple TKI has been reported, including crizotinib, lorlatinib, taletrectinib, and entrectinib, there has been no reported case of repotrectinib resistance.^A262066

On November 15th, 2023, the FDA approved repotrectinib under the brand name Augtyro for the treatment of locally advanced or metastatic ROS1-Positive NSCLC. This approval is based on favorable results from the TRIDENT-1 study, where the objective response rate was 79% in TKI-naive patients and 38% in TKI-pretreated patients respectively.^L48741

Struktur Molekul 2D

Berat 355.373

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 repotrectinib mean terminal half-life is approximately 50.6 h for patients with cancer following a single dose. The steady-state repotrectinib terminal half-life is approximately 35.4 h for patients with cancer.[L48711]

Volume Distribusi The geometric mean (CV%) apparent volume of distribution (Vz/F) was 432 L (55.9%) in patients with cancer following a single 160 mg oral dose of repotrectinib.[L48711]

Klirens (Clearance) The geometric mean (CV%) apparent oral clearance (CL/F) was 15.9 L/h (45.5%) in patients with cancer following a single 160 mg oral dose of repotrectinib.[L48711]

Absorpsi

The geometric mean (CV%) of repotrectinib steady state peak concentration (C_max,ss) is 713 (32.5%) ng/mL and the area under the time concentration curve (AUC_0-24h,ss) is 7210 (40.1%) ng•h/mL following the approved recommended twice daily dosage in patients with cancer. Repotrectinib C_max and AUC_0-inf increases approximately dose-proportional (but less than linear with estimated slopes of 0.78 and 0.70, respectively) over the single dose range of 40 mg to 240 mg (0.25 to 1.5 times the approved recommended dosage). Steady-state PK was time-dependent with an autoinduction of CYP3A4. Steady-state is achieved within 14 days of daily administration of 160 mg.^L48711 The geometric mean (CV%) absolute bioavailability of repotrectinib is 45.7% (19.6%). Peak repotrectinib concentration occurred at approximately 2 to 3 hours post a single oral dose of 40 mg to 240 mg (0.25 to 1.5 times the approved recommended dosage) under fasted conditions.^L48711 No clinically significant differences in repotrectinib pharmacokinetics were observed in patients with cancer following administration of a high-fat meal (approximately 800-1000 calories, 50% fat).^L48711

Metabolisme

Repotrectinib is primarily metabolized by CYP3A4 followed by secondary glucuronidation.^L48711

Rute Eliminasi

Following a single oral 160 mg dose of radiolabeled repotrectinib, 4.84% (0.56% as unchanged) was recovered in urine and 88.8% (50.6% unchanged) in feces.^L48711

Interaksi Makanan

1 Data

1. Take with or without food. Take repotrectinib at about the same time each day with or without food.

Interaksi Obat

759 Data

Ranolazine	The metabolism of Ranolazine can be increased when combined with Repotrectinib.
Aripiprazole	The metabolism of Aripiprazole can be increased when combined with Repotrectinib.
Aripiprazole lauroxil	The metabolism of Aripiprazole lauroxil can be increased when combined with Repotrectinib.
Eliglustat	The metabolism of Eliglustat can be decreased when combined with Repotrectinib.
Ibrutinib	The metabolism of Ibrutinib can be decreased when combined with Repotrectinib.
Cilostazol	The metabolism of Cilostazol can be decreased when combined with Repotrectinib.
Colchicine	The serum concentration of Colchicine can be increased when it is combined with Repotrectinib.
Iloperidone	The metabolism of Iloperidone can be decreased when combined with Repotrectinib.
Retapamulin	The metabolism of Retapamulin can be decreased when combined with Repotrectinib.
Tofacitinib	The metabolism of Tofacitinib can be decreased when combined with Repotrectinib.
Vardenafil	The metabolism of Vardenafil can be decreased when combined with Repotrectinib.
Eszopiclone	The serum concentration of Eszopiclone can be decreased when it is combined with Repotrectinib.
Zopiclone	The metabolism of Zopiclone can be decreased when combined with Repotrectinib.
Irinotecan	The risk or severity of neutropenia can be increased when Repotrectinib is combined with Irinotecan.
Lovastatin	The metabolism of Lovastatin can be decreased when combined with Repotrectinib.
Alfuzosin	The metabolism of Alfuzosin can be decreased when combined with Repotrectinib.
Alprazolam	The metabolism of Alprazolam can be decreased when combined with Repotrectinib.
Ifosfamide	The metabolism of Ifosfamide can be increased when combined with Repotrectinib.
Perampanel	The metabolism of Perampanel can be increased when combined with Repotrectinib.
Warfarin	The serum concentration of Warfarin can be decreased when it is combined with Repotrectinib.
Acenocoumarol	The serum concentration of Acenocoumarol can be decreased when it is combined with Repotrectinib.
(R)-warfarin	The serum concentration of (R)-warfarin can be increased when it is combined with Repotrectinib.
R,S-Warfarin alcohol	The serum concentration of R,S-Warfarin alcohol can be increased when it is combined with Repotrectinib.
S,R-Warfarin alcohol	The serum concentration of S,R-Warfarin alcohol can be increased when it is combined with Repotrectinib.
(S)-Warfarin	The serum concentration of (S)-Warfarin can be increased when it is combined with Repotrectinib.
Midazolam	The serum concentration of Midazolam can be increased when it is combined with Repotrectinib.
Tacrolimus	The serum concentration of Tacrolimus can be increased when it is combined with Repotrectinib.
Atorvastatin	The metabolism of Atorvastatin can be decreased when combined with Repotrectinib.
Eluxadoline	The serum concentration of Eluxadoline can be increased when it is combined with Repotrectinib.
Lumacaftor	The serum concentration of Repotrectinib can be increased when it is combined with Lumacaftor.
Erlotinib	The serum concentration of Erlotinib can be decreased when it is combined with Repotrectinib.
Phenytoin	The serum concentration of Repotrectinib can be decreased when it is combined with Phenytoin.
Pentobarbital	The serum concentration of Repotrectinib can be decreased when it is combined with Pentobarbital.
Carbamazepine	The serum concentration of Repotrectinib can be decreased when it is combined with Carbamazepine.
Mitotane	The serum concentration of Repotrectinib can be decreased when it is combined with Mitotane.
Primidone	The serum concentration of Repotrectinib can be decreased when it is combined with Primidone.
Rifampin	The serum concentration of Repotrectinib can be decreased when it is combined with Rifampicin.
Phenobarbital	The serum concentration of Repotrectinib can be decreased when it is combined with Phenobarbital.
Rifapentine	The serum concentration of Repotrectinib can be decreased when it is combined with Rifapentine.
Dexamethasone	The serum concentration of Repotrectinib can be decreased when it is combined with Dexamethasone.
Fosphenytoin	The serum concentration of Repotrectinib can be decreased when it is combined with Fosphenytoin.
St. John's Wort	The serum concentration of Repotrectinib can be decreased when it is combined with St. John's Wort.
Midostaurin	The serum concentration of Repotrectinib can be increased when it is combined with Midostaurin.
Enzalutamide	The serum concentration of Repotrectinib can be decreased when it is combined with Enzalutamide.
Apalutamide	The serum concentration of Repotrectinib can be decreased when it is combined with Apalutamide.
Cyclosporine	The serum concentration of Repotrectinib can be increased when it is combined with Cyclosporine.
Fluvoxamine	The serum concentration of Repotrectinib can be increased when it is combined with Fluvoxamine.
Fluconazole	The serum concentration of Repotrectinib can be increased when it is combined with Fluconazole.
Erythromycin	The serum concentration of Repotrectinib can be increased when it is combined with Erythromycin.
Ziprasidone	The serum concentration of Repotrectinib can be increased when it is combined with Ziprasidone.
Isradipine	The serum concentration of Repotrectinib can be increased when it is combined with Isradipine.
Diltiazem	The serum concentration of Repotrectinib can be increased when it is combined with Diltiazem.
Clozapine	The serum concentration of Clozapine can be increased when it is combined with Repotrectinib.
Haloperidol	The serum concentration of Haloperidol can be increased when it is combined with Repotrectinib.
Ciprofloxacin	The serum concentration of Repotrectinib can be increased when it is combined with Ciprofloxacin.
Voriconazole	The serum concentration of Repotrectinib can be increased when it is combined with Voriconazole.
Nicardipine	The serum concentration of Repotrectinib can be increased when it is combined with Nicardipine.
Verapamil	The serum concentration of Repotrectinib can be increased when it is combined with Verapamil.
Aprepitant	The serum concentration of Repotrectinib can be increased when it is combined with Aprepitant.
Isoniazid	The serum concentration of Repotrectinib can be increased when it is combined with Isoniazid.
Primaquine	The serum concentration of Repotrectinib can be increased when it is combined with Primaquine.
Miconazole	The serum concentration of Repotrectinib can be increased when it is combined with Miconazole.
Danazol	The serum concentration of Repotrectinib can be increased when it is combined with Danazol.
Fusidic acid	The serum concentration of Repotrectinib can be increased when it is combined with Fusidic acid.
Zimelidine	The serum concentration of Repotrectinib can be increased when it is combined with Zimelidine.
Dronedarone	The serum concentration of Repotrectinib can be increased when it is combined with Dronedarone.
Milnacipran	The serum concentration of Repotrectinib can be increased when it is combined with Milnacipran.
Simeprevir	The serum concentration of Repotrectinib can be increased when it is combined with Simeprevir.
Isavuconazonium	The serum concentration of Repotrectinib can be increased when it is combined with Isavuconazonium.
Desvenlafaxine	The serum concentration of Repotrectinib can be increased when it is combined with Desvenlafaxine.
Nilvadipine	The serum concentration of Repotrectinib can be increased when it is combined with Nilvadipine.
Seproxetine	The serum concentration of Repotrectinib can be increased when it is combined with Seproxetine.
Crizotinib	The serum concentration of Repotrectinib can be increased when it is combined with Crizotinib.
Linagliptin	The serum concentration of Repotrectinib can be increased when it is combined with Linagliptin.
Indalpine	The serum concentration of Repotrectinib can be increased when it is combined with Indalpine.
Netupitant	The serum concentration of Repotrectinib can be increased when it is combined with Netupitant.
Barnidipine	The serum concentration of Repotrectinib can be increased when it is combined with Barnidipine.
Benidipine	The serum concentration of Repotrectinib can be increased when it is combined with Benidipine.
Venetoclax	The serum concentration of Repotrectinib can be increased when it is combined with Venetoclax.
Isavuconazole	The serum concentration of Repotrectinib can be increased when it is combined with Isavuconazole.
Fosnetupitant	The serum concentration of Repotrectinib can be increased when it is combined with Fosnetupitant.
Berotralstat	The serum concentration of Berotralstat can be increased when it is combined with Repotrectinib.
Nelfinavir	The serum concentration of Repotrectinib can be increased when it is combined with Nelfinavir.
Indinavir	The serum concentration of Repotrectinib can be increased when it is combined with Indinavir.
Terfenadine	The serum concentration of Repotrectinib can be increased when it is combined with Terfenadine.
Ritonavir	The serum concentration of Repotrectinib can be increased when it is combined with Ritonavir.
Efavirenz	The serum concentration of Repotrectinib can be increased when it is combined with Efavirenz.
Ergotamine	The serum concentration of Repotrectinib can be increased when it is combined with Ergotamine.
Amprenavir	The serum concentration of Repotrectinib can be increased when it is combined with Amprenavir.
Delavirdine	The serum concentration of Repotrectinib can be increased when it is combined with Delavirdine.
Methimazole	The serum concentration of Repotrectinib can be increased when it is combined with Methimazole.
Conivaptan	The serum concentration of Repotrectinib can be increased when it is combined with Conivaptan.
Tipranavir	The serum concentration of Repotrectinib can be increased when it is combined with Tipranavir.
Telithromycin	The serum concentration of Repotrectinib can be increased when it is combined with Telithromycin.
Ketoconazole	The serum concentration of Repotrectinib can be increased when it is combined with Ketoconazole.
Atazanavir	The serum concentration of Repotrectinib can be increased when it is combined with Atazanavir.
Amiodarone	The serum concentration of Repotrectinib can be increased when it is combined with Amiodarone.
Nefazodone	The serum concentration of Repotrectinib can be increased when it is combined with Nefazodone.
Itraconazole	The serum concentration of Repotrectinib can be increased when it is combined with Itraconazole.
Clarithromycin	The serum concentration of Repotrectinib can be increased when it is combined with Clarithromycin.

Target Protein

Proto-oncogene tyrosine-protein kinase ROS ROS1

High affinity nerve growth factor receptor NTRK1

BDNF/NT-3 growth factors receptor NTRK2

NT-3 growth factor receptor NTRK3

Referensi & Sumber

Artikel (PubMed)

PMID: 32269053
Yun MR, Kim DH, Kim SY, Joo HS, Lee YW, Choi HM, Park CW, Heo SG, Kang HN, Lee SS, Schoenfeld AJ, Drilon A, Kang SG, Shim HS, Hong MH, Cui JJ, Kim HR, Cho BC: Repotrectinib Exhibits Potent Antitumor Activity in Treatment-Naive and Solvent-Front-Mutant ROS1-Rearranged Non-Small Cell Lung Cancer. Clin Cancer Res. 2020 Jul 1;26(13):3287-3295. doi: 10.1158/1078-0432.CCR-19-2777. Epub 2020 Apr 8.
PMID: 34625502
Murray BW, Rogers E, Zhai D, Deng W, Chen X, Sprengeler PA, Zhang X, Graber A, Reich SH, Stopatschinskaja S, Solomon B, Besse B, Drilon A: Molecular Characteristics of Repotrectinib That Enable Potent Inhibition of TRK Fusion Proteins and Resistant Mutations. Mol Cancer Ther. 2021 Dec;20(12):2446-2456. doi: 10.1158/1535-7163.MCT-21-0632. Epub 2021 Oct 8.
PMID: 34907086
Keddy C, Shinde P, Jones K, Kaech S, Somwar R, Shinde U, Davare MA: Resistance Profile and Structural Modeling of Next-Generation ROS1 Tyrosine Kinase Inhibitors. Mol Cancer Ther. 2022 Feb;21(2):336-346. doi: 10.1158/1535-7163.MCT-21-0395. Epub 2021 Dec 14.

Link

Contoh Produk & Brand

Produk: 2 • International brands: 0

Produk

Augtyro

Capsule • 40 mg/1 • Oral • US • Approved
Augtyro

Capsule • 160 mg/1 • Oral • US • Approved

Sekuens Gen/Protein (FASTA)

Sekuens dimuat saat dibutuhkan agar halaman tetap ringan.