Peringatan Keamanan

Based on acute intravenous dose toxicity studies, the lethal dose to 50% of animals was estimated to be 42 mg/kg in mice, 14 mg/kg in rats, and 4 mg/kg in dogs L1710.

Myelosuppression, with the primary clinical manifestation of neutropenia and leucopenia, is the dose-limiting toxicity of this drug. In addition to this, mucositis, nausea, vomiting, and alopecia are frequent. Hepatopathy, observed with elevated bilirubin concentrations, occurs less frequently. Cardiotoxicity is a major adverse effect of the anthracycline antibiotics and may be acute or chronic; in the acute setting, electrocardiographic (ECG) abnormalities may be observed, demonstrating ST-T elevations and arrhythmias, however, chronic cardiotoxicity poses a serious risk that may be lethal due to the slow development of irreversible, cardiomyopathy. The occurrence of toxicity shows a significant interindividual variation, and for this reason, the pharmacokinetics and pharmacodynamics of anthracyclines have been heavily investigated in order to identify models that may be used in the clinical setting to prevent the development of serious toxicity, mainly leucopenia, and maximize tumor exposure A32142. Interestingly, a recent study was done to further examine genetic predisposition neutropenia/amrubicin toxicity. It was determined that C3435T polymorphisms of the ABCB1 gene might be able to predict severe amrubicin-induced neutropenia A32147.

Secondary alcohol metabolites of earlier generation anthracyclines have been shown to lead to cardiac toxicity which is a major toxicity of conventional anthracyclines and thus limits the amount that can be delivered safely to patients.
Clinical manifestations of toxicity observed on the acute and repeated administration of amrubicin in rats and dogs were dose-related and reversible including fecal changes (mucoid or bloody feces/diarrhea), body weight decreases, decreased food consumption, decreased activity, and alopecia. Similar findings were observed at doses of doxorubicin approximately one half those of amrubicin L1710.

Amrubicin

DB06263

small molecule investigational

Deskripsi

Amrubicin is a third-generation synthetic anthracycline currently in development for the treatment of small cell lung cancer. Pharmion licensed the rights to Amrubicin in November 2006. In 2002, Amrubicin was approved and launched for sale in Japan based on Phase 2 efficacy data in both SCLC and NSCLC. Since January 2005, Amrubicin has been marketed by Nippon Kayaku, a Japanese pharmaceutical firm focused on oncology, which licensed Japanese marketing rights from Dainippon Sumitomo, the original developer of Amrubicin L1714, L1716.

Struktur Molekul 2D

Berat 483.473
Wujud solid

Peta Jejaring Molekuler
Legenda: Obat • Target • Gen • Enzim • (Panah → menunjukkan arah efek / relasi) • Transporter • Carrier

Profil Farmakokinetik

Waktu Paruh (Half-Life) 20-30 h [A32143] In a study of dogs, Amrubicin plasma concentrations followed a biphasic pattern with peak concentrations observed immediately after dosing followed by ? and ? half-lives (t1/2) ± SD of 0.06 ± 0.01 and 2.0 ± 0.3 hours, respectively [L1710].
Volume Distribusi Moderate volume of distribution (1.4 times total body water) [L1710].
Klirens (Clearance) The plasma pharmacokinetics of amrubicin in cancer patients are characterized by low total clearance (22% of total liver blood flow) [L1710].

Absorpsi

Peak plasma concentrations of the active metabolite amrubicinol were observed from immediately after administration of amrubicin to 1h after administration. Plasma concentrations of amrubicinol were low compared with amrubicin plasma concentrations. The plasma amrubicinol AUC (area under the curve) was approximately 10-fold lower than the amrubicin plasma AUC. Concentrations of amrubicinol were higher in RBCs as compared with plasma. Amrubicinol AUCs ranged from 2.5-fold to 57.9-fold higher in red blood cells (RBCs) compared to plasma. Because amrubicinol distributes itself into RBCs more than amrubicin, the concentrations of amrubicinol and amrubicin in RBCs were quite similar. The AUC of amrubicinol in RBCs was approximately twofold lower than the amrubicin RBC AUC L1713. In one study, after repeated daily amrubicin administration, amrubicinol accumulation was observed in plasma and RBCs. On day 3, the amrubicinol plasma AUC was 1.2-fold to 6-fold higher than day 1 values; the RBC AUC was 1.2-fold to 1.7-fold higher than day 1 values. After 5 consecutive daily doses, plasma and RBC amrubicinol AUCs were 1.2-fold to 2.0-fold higher than day 1 values L1713.

Metabolisme

The primary metabolite (amrubicinol) in rats and dogs is a product of reduction by cytoplasmic carbonyl reductase at the C-13 carbonyl group. Other enzymes participating in the metabolism of amrubicin and amrubicinol were nicotinamide adenine dinucleotide phosphate, reduced form (NADPH)–P450 reductase and nicotinamide adenine dinucleotide phosphate (NADPH)-quinone oxidoreductase. Twelve additional metabolites were detected in vivo and in vitro in one study L1710. Peak plasma concentrations of the active metabolite amrubicinol were observed from immediately after dosing to 1 hour after dosing L1710. These included four aglycone metabolites, two amrubicinol glucuronides, deaminated amrubicin, and five highly polar unknown metabolites. In vitro cell growth inhibitory activity of the minor metabolites was substantially lower than that of amrubicinol. Excretion of amrubicin and its metabolites is primarily hepatobiliary. Enterohepatic recycling was demonstrated in rats.

Rute Eliminasi

In one study, urinary excretion of amrubicin and amrubicinol after ingestion of amrubicin accounted for 2.7% to 19.6% of the administered dose. The amount of excreted amrubicinol was approximately 10-fold greater than excreted amrubicin L1710. Excretion of amrubicin and its metabolites is primarily hepatobiliary. Enterohepatic recycling was demonstrated in rats L1710.

Interaksi Obat

39 Data
Darbepoetin alfa The risk or severity of Thrombosis can be increased when Darbepoetin alfa is combined with Amrubicin.
Erythropoietin The risk or severity of Thrombosis can be increased when Erythropoietin is combined with Amrubicin.
Peginesatide The risk or severity of Thrombosis can be increased when Peginesatide is combined with Amrubicin.
Methoxy polyethylene glycol-epoetin beta The risk or severity of Thrombosis can be increased when Methoxy polyethylene glycol-epoetin beta is combined with Amrubicin.
Lidocaine The risk or severity of methemoglobinemia can be increased when Amrubicin is combined with Lidocaine.
Ropivacaine The risk or severity of methemoglobinemia can be increased when Amrubicin is combined with Ropivacaine.
Bupivacaine The risk or severity of methemoglobinemia can be increased when Amrubicin is combined with Bupivacaine.
Cinchocaine The risk or severity of methemoglobinemia can be increased when Amrubicin is combined with Cinchocaine.
Dyclonine The risk or severity of methemoglobinemia can be increased when Amrubicin is combined with Dyclonine.
Procaine The risk or severity of methemoglobinemia can be increased when Amrubicin is combined with Procaine.
Prilocaine The risk or severity of methemoglobinemia can be increased when Amrubicin is combined with Prilocaine.
Proparacaine The risk or severity of methemoglobinemia can be increased when Amrubicin is combined with Proparacaine.
Meloxicam The risk or severity of methemoglobinemia can be increased when Amrubicin is combined with Meloxicam.
Oxybuprocaine The risk or severity of methemoglobinemia can be increased when Amrubicin is combined with Oxybuprocaine.
Cocaine The risk or severity of methemoglobinemia can be increased when Amrubicin is combined with Cocaine.
Mepivacaine The risk or severity of methemoglobinemia can be increased when Amrubicin is combined with Mepivacaine.
Levobupivacaine The risk or severity of methemoglobinemia can be increased when Amrubicin is combined with Levobupivacaine.
Diphenhydramine The risk or severity of methemoglobinemia can be increased when Amrubicin is combined with Diphenhydramine.
Benzocaine The risk or severity of methemoglobinemia can be increased when Amrubicin is combined with Benzocaine.
Chloroprocaine The risk or severity of methemoglobinemia can be increased when Amrubicin is combined with Chloroprocaine.
Phenol The risk or severity of methemoglobinemia can be increased when Amrubicin is combined with Phenol.
Tetrodotoxin The risk or severity of methemoglobinemia can be increased when Amrubicin is combined with Tetrodotoxin.
Benzyl alcohol The risk or severity of methemoglobinemia can be increased when Amrubicin is combined with Benzyl alcohol.
Capsaicin The risk or severity of methemoglobinemia can be increased when Amrubicin is combined with Capsaicin.
Etidocaine The risk or severity of methemoglobinemia can be increased when Amrubicin is combined with Etidocaine.
Articaine The risk or severity of methemoglobinemia can be increased when Amrubicin is combined with Articaine.
Tetracaine The risk or severity of methemoglobinemia can be increased when Amrubicin is combined with Tetracaine.
Propoxycaine The risk or severity of methemoglobinemia can be increased when Amrubicin is combined with Propoxycaine.
Pramocaine The risk or severity of methemoglobinemia can be increased when Amrubicin is combined with Pramocaine.
Butamben The risk or severity of methemoglobinemia can be increased when Amrubicin is combined with Butamben.
Butacaine The risk or severity of methemoglobinemia can be increased when Amrubicin is combined with Butacaine.
Oxetacaine The risk or severity of methemoglobinemia can be increased when Amrubicin is combined with Oxetacaine.
Ethyl chloride The risk or severity of methemoglobinemia can be increased when Amrubicin is combined with Ethyl chloride.
Butanilicaine The risk or severity of methemoglobinemia can be increased when Amrubicin is combined with Butanilicaine.
Metabutethamine The risk or severity of methemoglobinemia can be increased when Amrubicin is combined with Metabutethamine.
Quinisocaine The risk or severity of methemoglobinemia can be increased when Amrubicin is combined with Quinisocaine.
Nelarabine The risk or severity of adverse effects can be increased when Nelarabine is combined with Amrubicin.
Ambroxol The risk or severity of methemoglobinemia can be increased when Amrubicin is combined with Ambroxol.
Etrasimod The risk or severity of immunosuppression can be increased when Amrubicin is combined with Etrasimod.

Target Protein

DNA topoisomerase 2-alpha TOP2A
DNA

Referensi & Sumber

Artikel (PubMed)
  • PMID: 18463964
    Katou M, Soga N, Onishi T, Arima K, Sugimura Y: Small cell carcinoma of the prostate treated with amrubicin. Int J Clin Oncol. 2008 Apr;13(2):169-72. doi: 10.1007/s10147-007-0702-x. Epub 2008 May 8.
  • PMID: 17628745
    Kurata T, Okamoto I, Tamura K, Fukuoka M: Amrubicin for non-small-cell lung cancer and small-cell lung cancer. Invest New Drugs. 2007 Oct;25(5):499-504. Epub 2007 Jul 13.
  • PMID: 16418065
    Tani N, Yabuki M, Komuro S, Kanamaru H: Characterization of the enzymes involved in the in vitro metabolism of amrubicin hydrochloride. Xenobiotica. 2005 Dec;35(12):1121-33. doi: 10.1080/00498250500342746 .
  • PMID: 17410034
    Ettinger DS: Amrubicin for the treatment of small cell lung cancer: does effectiveness cross the Pacific? J Thorac Oncol. 2007 Feb;2(2):160-5. doi: /JTO.0b013e31802f1cd9.
  • PMID: 12074691
    Danesi R, Fogli S, Gennari A, Conte P, Del Tacca M: Pharmacokinetic-pharmacodynamic relationships of the anthracycline anticancer drugs. Clin Pharmacokinet. 2002;41(6):431-44. doi: 10.2165/00003088-200241060-00004.
  • PMID: 2611038
    Eksborg S: Pharmacokinetics of anthracyclines. Acta Oncol. 1989;28(6):873-6.
  • PMID: 9914793
    Hanada M, Mizuno S, Fukushima A, Saito Y, Noguchi T, Yamaoka T: A new antitumor agent amrubicin induces cell growth inhibition by stabilizing topoisomerase II-DNA complex. Jpn J Cancer Res. 1998 Nov;89(11):1229-38.
  • PMID: 18054347
    Hira A, Watanabe H, Maeda Y, Yokoo K, Sanematsu E, Fujii J, Sasaki J, Hamada A, Saito H: Role of P-glycoprotein in accumulation and cytotoxicity of amrubicin and amrubicinol in MDR1 gene-transfected LLC-PK1 cells and human A549 lung adenocarcinoma cells. Biochem Pharmacol. 2008 Feb 15;75(4):973-80. doi: 10.1016/j.bcp.2007.10.023. Epub 2007 Oct 30.
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