Peringatan Keamanan

The most severe toxic reaction seen in patients is progressive multifocal leukoencephalopathy.^L39789

Progressive multifocal leukoencephalopathy (PML) follows infection by the JC virus (which is not related to Creutzfeldt-Jakob disease). Symptoms of this condition begin insidiously and usually worsen progressively. The symptoms vary depending on which region of the brain is infected. In about two out of three patients, mental function deteriorates rapidly, leading to dementia. Speaking and walking may become increasingly difficult. Vision may be impaired, and total blindness may occur. Rarely, headaches and seizures can occur, mainly in immunocompromised patients. The most serious sequela of this condition is death.^L1743

Common adverse effects of Adcetris may include: neutropenia, anemia, peripheral neuropathy, nausea, fatigue, constipation, diarrhea, vomiting, and fever. In one trial, neutropenia occurred in 91 percent of patients treated with Adcetris plus chemotherapy, which was associated with a 19 percent rate of febrile neutropenia (neutropenia and fever).^L1737 Preventive treatment with G-CSF, a growth factor for the bone marrow to produce white blood cells, is recommended with Adcetris plus chemotherapy for the first-line treatment of Stage III or IV cHL.^L1737

Adcetris has a boxed warning that emphasizes the risk of John Cunningham virus infection leading to progressive multifocal leukoencephalopathy, or PML, a rare but serious brain infection that may be lethal.

Serious risks of Adcetris include peripheral neuropathy; severe allergic (anaphylaxis) or infusion-site reactions; damage to the blood, lungs and liver (hematologic, pulmonary and hepato-toxicities); severe/opportunistic infections; metabolic abnormalities (tumor lysis syndrome); dermatologic reactions and gastrointestinal complications. Adcetris may cause harm to the fetus and newborn baby; women should be warned of the potential risk to the fetus and to use effective contraception, and to avoid breastfeeding while taking Adcetris.^L1737

MMAE was found to be genotoxic in the rat bone marrow micronucleus study through an aneugenic mechanism. This effect is consistent with the pharmacological effect of MMAE as a microtubule-disrupting drug. Fertility studies with Brentuximab vedotin or MMAE have not been conducted. Despite this, results of repeat-dose toxicity studies in rats suggest the potential for Brentuximab vedotin to have a negative effect on male reproductive function and fertility. In a 4-week repeated-dose toxicity study in rats with weekly dosing at 0.5, 5 or 10 mg/kg brentuximab vedotin, seminiferous tubule degeneration, Sertoli cell vacuolation, reduced spermatogenesis, and aspermia were observed.^L1737 Effects in animals were seen mostly at 5 and 10 mg/kg doses of brentuximab vedotin. These dosages are approximately 3 and 6-fold the human recommended dose of 1.8 mg/kg, respectively, based on individual body weight.^L39789

Brentuximab vedotin

DB08870

biotech approved investigational

Deskripsi

Brentuximab vedotin, also known as Adcetris®, is an antibody-drug conjugate that combines an anti-CD30 antibody with the drug monomethyl auristatin E (MMAE). It is an anti-neoplastic agent used in the treatment of Hodgkin's lymphoma and systemic anaplastic large-cell lymphoma. Brentuximab vedotin was initially approved in 2011. In January 2012, the drug label was revised with a boxed warning of a condition known as progressive multifocal leukoencephalopathy and death due to opportunistic JC virus infection post-treatment.^L1737

The U.S. Food and Drug Administration approved Adcetris in March 2018 to treat adult patients with previously untreated stage III or IV classical Hodgkin lymphoma (cHL) in combination with chemotherapy.^L1737

Adcetris has also been previously approved by the FDA to treat Hodgkin's lymphoma after relapse, Hodgkin's lymphoma after stem cell transplantation when a patient has a high risk of relapse or progression, systemic anaplastic large cell lymphoma (ALCL) after the failure of other treatment regimens, and primary cutaneous ALCL after failure of other treatment regimens.^L1737

Lymphoma is a malignancy that begins in the lymphatic system, which helps to combat infection and disease. Lymphoma may begin anywhere in the body and can spread to nearby lymph nodes. The two main types of lymphoma are Hodgkin lymphoma (also called Hodgkin disease) and non-Hodgkin lymphoma. Most individuals with Hodgkin's lymphoma have the classical type. In this type of lymphoma, large, abnormal lymphocytes (a type of white blood cell) are found in the lymph nodes called Reed-Sternberg cells. With early diagnosis and intervention, patients with Hodgkin lymphoma normally experience long-term remission.^L1737

The ECHELON-1 study results demonstrated superior efficacy of the drug combined with a chemotherapy regimen compared to the previous standard of care. Importantly, bleomycin - a highly toxic agent - was completely removed from the regimen. This demonstrates meaningful progress in treatment for patients affected by this disease.^L1739

Struktur Molekul 2D

Struktur tidak tersedia

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 terminal half-life is approximately 4-6 days.[L39789]

Volume Distribusi MMAE is unlikely to displace or to be displaced by highly protein-bound drugs. In vitro studies show that MMAE is a substrate of P-gp and was not a potent inhibitor of P-gp.[L39789]

Klirens (Clearance) The liver is the primary route of clearance for MMAE. The pharmacokinetics and safety of Brentuximab vedotin and MMAE were examined after the administration of 1.2 mg/kg of Adcetris to patients with mild, moderate, and severe hepatic impairment. In patients with moderate and severe hepatic impairment, the rate of ?Grade 3 adverse reactions was 6/6 (100%) compared to 3/8 (38%) in patients with normal hepatic function.[L39789] It is recommended to avoid use in patients with severe renal impairment (CrCl <30mL/min).[L1742]

Absorpsi

Steady-state of the ADC is achieved within 21 days with every 3-week dosing of Adcetris. Minimal to no accumulation of ADC is observed with multiple doses at the every 3-week schedule. The time to maximum concentration for MMAE ranges from approximately 1 to 3 days. Similar to the ADC, steady-state of MMAE is achieved within 21 days with every 3-week dosing of Adcetris. MMAE exposures decrease with continued administration of Adcetris with about 50% to 80% of the exposure of the first dose being observed at future doses. The AUC of MMAE was measured to be approximately 2.2-fold higher in patients with hepatic impairment in comparison with patients with normal hepatic function.^L39789

Metabolisme

Data in both animals and humans suggest that only a small fraction of MMAE released from brentuximab vedotin is metabolized. In vitro data indicate that the MMAE metabolism that occurs is primarily via oxidation by CYP3A4/5. In vitro studies using human liver microsomes indicate that MMAE inhibits CYP3A4/5 but not other CYP isoforms. MMAE did not induce any major CYP450 enzymes in primary cultures of human hepatocytes.^L39789

Rute Eliminasi

This drug appears follow metabolite kinetics, with the elimination of appearing to be limited by its rate of release from the antibody-drug conjugate (ADC). An excretion study was done in patients receiving a dose of 1.8 mg/kg of Adcetris. About 24% of the total MMAE ingested as part of the ADC during an ADCETRIS infusion was recovered in both urine and feces over a 7-day time frame. Of the recovered MMAE, approximately 72% was found in the feces and the majority of the excreted MMAE was excreted as unchanged drug.^L39789

Interaksi Makanan

2 Data

1. Exercise caution with grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which may increase the serum concentration of monomethyl auristatin E (MMAE), the antitumor component of brentuximab vedotin.
2. Exercise caution with St. John's Wort. This herb induces CYP3A4 metabolism, which may reduce the serum concentration of monomethyl auristatin E (MMAE), the antitumor component of brentuximab vedotin.

Interaksi Obat

1208 Data

Denosumab	The risk or severity of adverse effects can be increased when Denosumab is combined with Brentuximab vedotin.
Peginterferon alfa-2a	The risk or severity of adverse effects can be increased when Peginterferon alfa-2a is combined with Brentuximab vedotin.
Interferon alfa-n1	The risk or severity of adverse effects can be increased when Interferon alfa-n1 is combined with Brentuximab vedotin.
Interferon alfa-n3	The risk or severity of adverse effects can be increased when Interferon alfa-n3 is combined with Brentuximab vedotin.
Peginterferon alfa-2b	The risk or severity of adverse effects can be increased when Peginterferon alfa-2b is combined with Brentuximab vedotin.
Interferon gamma-1b	The risk or severity of adverse effects can be increased when Interferon gamma-1b is combined with Brentuximab vedotin.
Interferon alfa-2a	The risk or severity of adverse effects can be increased when Interferon alfa-2a is combined with Brentuximab vedotin.
Gemtuzumab ozogamicin	The risk or severity of adverse effects can be increased when Gemtuzumab ozogamicin is combined with Brentuximab vedotin.
Pegaspargase	The risk or severity of adverse effects can be increased when Pegaspargase is combined with Brentuximab vedotin.
Interferon beta-1b	The risk or severity of adverse effects can be increased when Interferon beta-1b is combined with Brentuximab vedotin.
Interferon alfacon-1	The risk or severity of adverse effects can be increased when Interferon alfacon-1 is combined with Brentuximab vedotin.
Rituximab	The risk or severity of adverse effects can be increased when Rituximab is combined with Brentuximab vedotin.
Basiliximab	The risk or severity of adverse effects can be increased when Basiliximab is combined with Brentuximab vedotin.
Muromonab	The risk or severity of adverse effects can be increased when Muromonab is combined with Brentuximab vedotin.
Ibritumomab tiuxetan	The risk or severity of adverse effects can be increased when Ibritumomab tiuxetan is combined with Brentuximab vedotin.
Tositumomab	The risk or severity of adverse effects can be increased when Tositumomab is combined with Brentuximab vedotin.
Alemtuzumab	The risk or severity of adverse effects can be increased when Alemtuzumab is combined with Brentuximab vedotin.
Alefacept	The risk or severity of adverse effects can be increased when Alefacept is combined with Brentuximab vedotin.
Efalizumab	The risk or severity of adverse effects can be increased when Efalizumab is combined with Brentuximab vedotin.
Antithymocyte immunoglobulin (rabbit)	The risk or severity of adverse effects can be increased when Antithymocyte immunoglobulin (rabbit) is combined with Brentuximab vedotin.
Interferon alfa-2b	The risk or severity of adverse effects can be increased when Interferon alfa-2b is combined with Brentuximab vedotin.
Daclizumab	The risk or severity of adverse effects can be increased when Daclizumab is combined with Brentuximab vedotin.
Phenylalanine	The risk or severity of adverse effects can be increased when Phenylalanine is combined with Brentuximab vedotin.
Cladribine	Brentuximab vedotin may increase the immunosuppressive activities of Cladribine.
Carmustine	The risk or severity of adverse effects can be increased when Carmustine is combined with Brentuximab vedotin.
Chlorambucil	The risk or severity of adverse effects can be increased when Chlorambucil is combined with Brentuximab vedotin.
Raltitrexed	The risk or severity of adverse effects can be increased when Raltitrexed is combined with Brentuximab vedotin.
Mitomycin	The risk or severity of adverse effects can be increased when Mitomycin is combined with Brentuximab vedotin.
Floxuridine	The risk or severity of adverse effects can be increased when Floxuridine is combined with Brentuximab vedotin.
Tioguanine	The risk or severity of adverse effects can be increased when Tioguanine is combined with Brentuximab vedotin.
Dexrazoxane	The risk or severity of adverse effects can be increased when Dexrazoxane is combined with Brentuximab vedotin.
Trifluridine	The risk or severity of adverse effects can be increased when Trifluridine is combined with Brentuximab vedotin.
Gemcitabine	The risk or severity of adverse effects can be increased when Gemcitabine is combined with Brentuximab vedotin.
Epirubicin	The risk or severity of adverse effects can be increased when Epirubicin is combined with Brentuximab vedotin.
Lenalidomide	The risk or severity of adverse effects can be increased when Lenalidomide is combined with Brentuximab vedotin.
Altretamine	The risk or severity of adverse effects can be increased when Altretamine is combined with Brentuximab vedotin.
Zidovudine	The risk or severity of adverse effects can be increased when Zidovudine is combined with Brentuximab vedotin.
Cisplatin	The risk or severity of adverse effects can be increased when Cisplatin is combined with Brentuximab vedotin.
Oxaliplatin	The risk or severity of adverse effects can be increased when Oxaliplatin is combined with Brentuximab vedotin.
Fluorouracil	The risk or severity of adverse effects can be increased when Fluorouracil is combined with Brentuximab vedotin.
Propylthiouracil	The risk or severity of adverse effects can be increased when Propylthiouracil is combined with Brentuximab vedotin.
Pentostatin	The risk or severity of adverse effects can be increased when Pentostatin is combined with Brentuximab vedotin.
Linezolid	The risk or severity of adverse effects can be increased when Linezolid is combined with Brentuximab vedotin.
Clofarabine	The risk or severity of adverse effects can be increased when Clofarabine is combined with Brentuximab vedotin.
Pemetrexed	The risk or severity of adverse effects can be increased when Pemetrexed is combined with Brentuximab vedotin.
Fludrocortisone	The risk or severity of adverse effects can be increased when Fludrocortisone is combined with Brentuximab vedotin.
Mycophenolate mofetil	The risk or severity of adverse effects can be increased when Mycophenolate mofetil is combined with Brentuximab vedotin.
Sulfasalazine	The risk or severity of adverse effects can be increased when Sulfasalazine is combined with Brentuximab vedotin.
Dacarbazine	The risk or severity of adverse effects can be increased when Dacarbazine is combined with Brentuximab vedotin.
Temozolomide	The risk or severity of adverse effects can be increased when Temozolomide is combined with Brentuximab vedotin.
Penicillamine	The risk or severity of adverse effects can be increased when Penicillamine is combined with Brentuximab vedotin.
Mechlorethamine	The risk or severity of adverse effects can be increased when Mechlorethamine is combined with Brentuximab vedotin.
Azacitidine	The risk or severity of adverse effects can be increased when Azacitidine is combined with Brentuximab vedotin.
Carboplatin	The risk or severity of adverse effects can be increased when Carboplatin is combined with Brentuximab vedotin.
Azathioprine	The risk or severity of adverse effects can be increased when Azathioprine is combined with Brentuximab vedotin.
Hydroxyurea	The risk or severity of adverse effects can be increased when Hydroxyurea is combined with Brentuximab vedotin.
Mycophenolic acid	The risk or severity of adverse effects can be increased when Mycophenolic acid is combined with Brentuximab vedotin.
Mercaptopurine	The risk or severity of adverse effects can be increased when Mercaptopurine is combined with Brentuximab vedotin.
Thalidomide	The metabolism of Brentuximab vedotin can be increased when combined with Thalidomide.
Melphalan	The risk or severity of adverse effects can be increased when Melphalan is combined with Brentuximab vedotin.
Fludarabine	The risk or severity of adverse effects can be increased when Fludarabine is combined with Brentuximab vedotin.
Flucytosine	The risk or severity of adverse effects can be increased when Flucytosine is combined with Brentuximab vedotin.
Capecitabine	The risk or severity of adverse effects can be increased when Capecitabine is combined with Brentuximab vedotin.
Procarbazine	The risk or severity of adverse effects can be increased when Procarbazine is combined with Brentuximab vedotin.
Idarubicin	The risk or severity of adverse effects can be increased when Idarubicin is combined with Brentuximab vedotin.
Lomustine	The risk or severity of adverse effects can be increased when Lomustine is combined with Brentuximab vedotin.
Eculizumab	The risk or severity of adverse effects can be increased when Eculizumab is combined with Brentuximab vedotin.
Decitabine	The risk or severity of adverse effects can be increased when Decitabine is combined with Brentuximab vedotin.
Nelarabine	The risk or severity of adverse effects can be increased when Nelarabine is combined with Brentuximab vedotin.
Ciclesonide	The risk or severity of adverse effects can be increased when Ciclesonide is combined with Brentuximab vedotin.
Stepronin	The risk or severity of adverse effects can be increased when Stepronin is combined with Brentuximab vedotin.
Castanospermine	The risk or severity of adverse effects can be increased when Castanospermine is combined with Brentuximab vedotin.
Vorinostat	The risk or severity of adverse effects can be increased when Vorinostat is combined with Brentuximab vedotin.
2-Methoxyethanol	The risk or severity of adverse effects can be increased when 2-Methoxyethanol is combined with Brentuximab vedotin.
Brequinar	The risk or severity of adverse effects can be increased when Brequinar is combined with Brentuximab vedotin.
Pirfenidone	The risk or severity of adverse effects can be increased when Pirfenidone is combined with Brentuximab vedotin.
Interferon alfa	The risk or severity of adverse effects can be increased when Interferon alfa is combined with Brentuximab vedotin.
Glatiramer	The risk or severity of adverse effects can be increased when Glatiramer is combined with Brentuximab vedotin.
Briakinumab	The risk or severity of adverse effects can be increased when Briakinumab is combined with Brentuximab vedotin.
Human interferon omega-1	The risk or severity of adverse effects can be increased when Human interferon omega-1 is combined with Brentuximab vedotin.
Mepolizumab	The risk or severity of adverse effects can be increased when Mepolizumab is combined with Brentuximab vedotin.
Abetimus	The risk or severity of adverse effects can be increased when Abetimus is combined with Brentuximab vedotin.
Belatacept	The risk or severity of adverse effects can be increased when Belatacept is combined with Brentuximab vedotin.
Bendamustine	The risk or severity of adverse effects can be increased when Bendamustine is combined with Brentuximab vedotin.
Pralatrexate	The risk or severity of adverse effects can be increased when Pralatrexate is combined with Brentuximab vedotin.
Wortmannin	The risk or severity of adverse effects can be increased when Wortmannin is combined with Brentuximab vedotin.
Eribulin	The risk or severity of adverse effects can be increased when Brentuximab vedotin is combined with Eribulin.
Belimumab	The risk or severity of adverse effects can be increased when Brentuximab vedotin is combined with Belimumab.
Teriflunomide	The risk or severity of adverse effects can be increased when Brentuximab vedotin is combined with Teriflunomide.
Dimethyl fumarate	The risk or severity of adverse effects can be increased when Brentuximab vedotin is combined with Dimethyl fumarate.
Obinutuzumab	The risk or severity of adverse effects can be increased when Brentuximab vedotin is combined with Obinutuzumab.
Vedolizumab	The risk or severity of adverse effects can be increased when Brentuximab vedotin is combined with Vedolizumab.
Blinatumomab	The risk or severity of adverse effects can be increased when Brentuximab vedotin is combined with Blinatumomab.
Dinutuximab	The risk or severity of adverse effects can be increased when Brentuximab vedotin is combined with Dinutuximab.
Vilanterol	The risk or severity of adverse effects can be increased when Brentuximab vedotin is combined with Vilanterol.
Tixocortol	The risk or severity of adverse effects can be increased when Brentuximab vedotin is combined with Tixocortol.
Peginterferon beta-1a	The risk or severity of adverse effects can be increased when Brentuximab vedotin is combined with Peginterferon beta-1a.
Antilymphocyte immunoglobulin (horse)	The risk or severity of adverse effects can be increased when Brentuximab vedotin is combined with Antilymphocyte immunoglobulin (horse).
Fluprednisolone	The risk or severity of adverse effects can be increased when Brentuximab vedotin is combined with Fluprednisolone.
Tepoxalin	The risk or severity of adverse effects can be increased when Brentuximab vedotin is combined with Tepoxalin.

Target Protein

Tumor necrosis factor receptor superfamily member 8 TNFRSF8

Referensi & Sumber

Synthesis reference: Francisco JA, Cerveny CG, Meyer DL, Mixan BJ, Klussman K, Chace DF, Rejniak SX, Gordon KA, DeBlanc R, Toki BE, Law CL, Doronina SO, Siegall CB, Senter PD, Wahl AF: cAC10-vcMMAE, an anti-CD30-monomethyl auristatin E conjugate with potent and selective antitumor activity. Blood. 2003 Aug 15;102(4):1458-65. Epub 2003 Apr 24

Artikel (PubMed)

PMID: 12714494
Francisco JA, Cerveny CG, Meyer DL, Mixan BJ, Klussman K, Chace DF, Rejniak SX, Gordon KA, DeBlanc R, Toki BE, Law CL, Doronina SO, Siegall CB, Senter PD, Wahl AF: cAC10-vcMMAE, an anti-CD30-monomethyl auristatin E conjugate with potent and selective antitumor activity. Blood. 2003 Aug 15;102(4):1458-65. Epub 2003 Apr 24.
PMID: 29133014
Eichenauer DA, Plutschow A, Kreissl S, Sokler M, Hellmuth JC, Meissner J, Mathas S, Topp MS, Behringer K, Klapper W, Kuhnert G, Dietlein M, Kobe C, Fuchs M, Diehl V, Engert A, Borchmann P: Incorporation of brentuximab vedotin into first-line treatment of advanced classical Hodgkin's lymphoma: final analysis of a phase 2 randomised trial by the German Hodgkin Study Group. Lancet Oncol. 2017 Dec;18(12):1680-1687. doi: 10.1016/S1470-2045(17)30696-4. Epub 2017 Nov 10.
PMID: 24023323
Cao H, Yamamoto K, Yang LX, Weber R: Brentuximab vedotin: first-line agent for advanced Hodgkin lymphoma. Anticancer Res. 2013 Sep;33(9):3879-85.
PMID: 9826579
Horie R, Watanabe T: CD30: expression and function in health and disease. Semin Immunol. 1998 Dec;10(6):457-70. doi: 10.1006/smim.1998.0156.

Link

Contoh Produk & Brand

Produk: 3 • International brands: 0

Produk

Adcetris

Injection, powder, lyophilized, for solution • 50 mg/10.5mL • Intravenous • US • Approved
Adcetris

Powder, for solution • 50 mg / vial • Intravenous • Canada • Approved
Adcetris

Injection, powder, for solution • 50 mg • Intravenous • EU • Approved

Sekuens Gen/Protein (FASTA)

Sekuens dimuat saat dibutuhkan agar halaman tetap ringan.