Peringatan Keamanan

A single IV dose of 4,800 mg/m^2 was lethal in monkeys, and was associated with CNS signs including reduced/shallow respiration, reduced reflexes, and flaccid muscle tone. It is anticipated that overdosage would result in severe neurotoxicity (possibly including paralysis, coma), myelosuppression, and potentially death.

Nelarabine

DB01280

small molecule approved investigational

Deskripsi

Nelarabine is an antineoplastic agent that is typically used to treat acute T-cell lymphoblastic leukemia, particularly T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL), in both adult and pediatric patients whose disease has not responded to or has relapsed following at least two chemotherapy regimens.L40878 T-cell acute lymphoblastic leukemia and lymphoma are relatively rare T-cells malignancy, with only 20 to 25% of patients diagnosed with acute lymphoblastic leukemia and 1.7% of patients diagnosed with non-Hodgkin's lymphoma having this T-cells variation of the disease.A2332 Due to the rarity of these T-cell malignancies, nelarabine was first granted orphan drug status and a fast-track designation by the FDA to address the unmet therapeutic needs of these cancers.A2331

Nelarabine is a purine nucleoside analog converted to its corresponding arabinosylguanine nucleotide triphosphate (araGTP), resulting in the inhibition of DNA synthesis and cytotoxicity.L40878 Nelarabine preferentially accumulates in T-cells since T-cells have a higher expression of enzymes that convert nelarabine to the active purine analog form, making them effective against T-cells malignancies.A2331,AA2334,2335 Results from 2 phase 2 studies on adult and pediatric T-ALL/T-LBL indicated that nelarabine can yield a 13% complete response (CR) rate in pediatric patients and 18% in adult patients, albeit with serious hematological and neurological adverse events.A258719

Nelarabine was first granted accelerated approval by the FDA on October 28, 2005, and was manufactured under the trademark name ARRANON by GlaxoSmithKline.A15220 Subsequently, nelarabine was also approved by both Health Canada and European Medicines Agency in 2007 under the trademark name ATRIANCE.L45874,L45879

Struktur Molekul 2D

Berat 297.2673
Wujud solid

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

Profil Farmakokinetik

Waktu Paruh (Half-Life) Nelarabine and ara-G are rapidly eliminated from plasma with a mean half-life of 18 minutes and 3.2 hours, respectively, in adult patients.[L40878] For pediatric patients, the half-life of nelarabine and ara-G are 13 minutes and 2 hours, respectively.[L40878] Because the intracellular levels of ara-GTP were so prolonged, its elimination half-life could not be accurately estimated.[L40878]
Volume Distribusi Nelarabine and ara-G are extensively distributed throughout the body. For nelarabine, V<sub>ss</sub> values were 197 ± 216 L/m<sup>2</sup> in adult patients. For ara-G, V<sub>ss</sub>/F values were 50 ± 24 L/m<sup>2</sup> in adult patients.[L40878]
Klirens (Clearance) Renal clearance averaged 24 ± 23 L/h for nelarabine and 6.2 ± 5.0 L/h for ara-G in 21 adult patients. Combined Phase I pharmacokinetic data at nelarabine doses of 199 to 2,900 mg/m<sup>2</sup> (n = 66 adult patients) indicate that the mean clearance (CL) of nelarabine is 197 ± 189 L/h/m<sup>2</sup> on Day 1. The apparent clearance of ara-G (CL/F) is 10.5 ± 4.5 L/h/m<sup>2</sup> on Day 1.[L40878] For pediatric patients receiving at a dose of 104 to 2,900 mg/m<sup>2</sup>, the combined Phase I pharmacokinetic data indicate that the mean clearance (CL) of nelarabine is 259 ± 409 L/h/m<sup>2</sup>, 30% higher than in adult patients. The apparent clearance of ara-G on day 1 is also higher in pediatric patients than in adult patients, estimated to be 11.3 ± 4.2 L/h/m<sup>2</sup>.[L40878]

Absorpsi

Following intravenous administration of nelarabine to adult patients with refractory leukemia or lymphoma, plasma ara-G Cmax values generally occurred at the end of the nelarabine infusion and were generally higher than nelarabine Cmax values, suggesting rapid and extensive conversion of nelarabine to ara-G. Mean plasma nelarabine and ara-G Cmax values were 5.0 ± 3.0 mcg/mL and 31.4 ± 5.6 mcg/mL, respectively, after a 1,500 mg/m2 nelarabine dose infused over 2 hours in adult patients.L40878 The area under the concentration-time curve (AUC) of ara-G is 37 times higher than that for nelarabine on Day 1 after nelarabine IV infusion of 1,500 mg/m2 dose (162 ± 49 mcg.h/mL versus 4.4 ± 2.2 mcg.h/mL, respectively). Comparable Cmax and AUC values were obtained for nelarabine between Days 1 and 5 at the nelarabine adult dosage of 1,500 mg/m2, indicating that nelarabine does not accumulate after multiple dosing. There are not enough ara-G data to make a comparison between Day 1 and Day 5.L40878 After a nelarabine adult dose of 1,500 mg/m2, intracellular Cmax for ara-GTP appeared within 3 to 25 hours on Day 1. Exposure (AUC) to intracellular ara-GTP was 532 times higher than that for nelarabine and 14 times higher than that for ara-G (2,339 ± 2,628 mcg.h/mL versus 4.4 ± 2.2 mcg.h/mL and 162 ± 49 mcg.h/mL, respectively).L40878

Metabolisme

The principal route of metabolism for nelarabine is O-demethylation by adenosine deaminase to form ara-G, which undergoes hydrolysis to form guanine. In addition, some nelarabine is hydrolyzed to form methylguanine, which is O-demethylated to form guanine. Guanine is N-deaminated to form xanthine, which is further oxidized to yield uric acid.L40878 Ring opening of uric acid followed by further oxidation results in the formation of allantoin.L45833 Ring opening of uric acid followed by further oxidation results in the formation of allantoin.

Rute Eliminasi

Nelarabine and ara-G are partially eliminated by the kidneys.L40878 Mean urinary excretion of nelarabine and ara-G was 6.6 ± 4.7% and 27 ± 15% of the administered dose, respectively, in 28 adult patients over the 24 hours after nelarabine infusion on Day 1.L40878

Interaksi Obat

789 Data
Denosumab The risk or severity of adverse effects can be increased when Denosumab is combined with Nelarabine.
Etanercept The risk or severity of adverse effects can be increased when Etanercept is combined with Nelarabine.
Peginterferon alfa-2a The risk or severity of adverse effects can be increased when Peginterferon alfa-2a is combined with Nelarabine.
Interferon alfa-n1 The risk or severity of adverse effects can be increased when Interferon alfa-n1 is combined with Nelarabine.
Interferon alfa-n3 The risk or severity of adverse effects can be increased when Interferon alfa-n3 is combined with Nelarabine.
Peginterferon alfa-2b The risk or severity of adverse effects can be increased when Peginterferon alfa-2b is combined with Nelarabine.
Anakinra The risk or severity of adverse effects can be increased when Anakinra is combined with Nelarabine.
Interferon gamma-1b The risk or severity of adverse effects can be increased when Interferon gamma-1b is combined with Nelarabine.
Interferon alfa-2a The risk or severity of adverse effects can be increased when Interferon alfa-2a is combined with Nelarabine.
Aldesleukin The risk or severity of adverse effects can be increased when Aldesleukin is combined with Nelarabine.
Adalimumab The risk or severity of adverse effects can be increased when Adalimumab is combined with Nelarabine.
Gemtuzumab ozogamicin The risk or severity of adverse effects can be increased when Gemtuzumab ozogamicin is combined with Nelarabine.
Pegaspargase The risk or severity of adverse effects can be increased when Pegaspargase is combined with Nelarabine.
Infliximab The risk or severity of adverse effects can be increased when Infliximab is combined with Nelarabine.
Interferon beta-1b The risk or severity of adverse effects can be increased when Interferon beta-1b is combined with Nelarabine.
Interferon alfacon-1 The risk or severity of adverse effects can be increased when Interferon alfacon-1 is combined with Nelarabine.
Rituximab The risk or severity of adverse effects can be increased when Rituximab is combined with Nelarabine.
Basiliximab The risk or severity of adverse effects can be increased when Basiliximab is combined with Nelarabine.
Muromonab The risk or severity of adverse effects can be increased when Muromonab is combined with Nelarabine.
Ibritumomab tiuxetan The risk or severity of adverse effects can be increased when Ibritumomab tiuxetan is combined with Nelarabine.
Tositumomab The risk or severity of adverse effects can be increased when Tositumomab is combined with Nelarabine.
Alemtuzumab The risk or severity of adverse effects can be increased when Alemtuzumab is combined with Nelarabine.
Alefacept The risk or severity of adverse effects can be increased when Alefacept is combined with Nelarabine.
Efalizumab The risk or severity of adverse effects can be increased when Efalizumab is combined with Nelarabine.
Antithymocyte immunoglobulin (rabbit) The risk or severity of adverse effects can be increased when Antithymocyte immunoglobulin (rabbit) is combined with Nelarabine.
Interferon alfa-2b The risk or severity of adverse effects can be increased when Interferon alfa-2b is combined with Nelarabine.
Daclizumab The risk or severity of adverse effects can be increased when Daclizumab is combined with Nelarabine.
Phenylalanine The risk or severity of adverse effects can be increased when Phenylalanine is combined with Nelarabine.
Flunisolide The risk or severity of adverse effects can be increased when Flunisolide is combined with Nelarabine.
Bortezomib The risk or severity of adverse effects can be increased when Bortezomib is combined with Nelarabine.
Cladribine Nelarabine may increase the immunosuppressive activities of Cladribine.
Carmustine The risk or severity of adverse effects can be increased when Carmustine is combined with Nelarabine.
Amsacrine The risk or severity of adverse effects can be increased when Amsacrine is combined with Nelarabine.
Bleomycin The risk or severity of adverse effects can be increased when Bleomycin is combined with Nelarabine.
Chlorambucil The risk or severity of adverse effects can be increased when Chlorambucil is combined with Nelarabine.
Raltitrexed The risk or severity of adverse effects can be increased when Raltitrexed is combined with Nelarabine.
Mitomycin The risk or severity of adverse effects can be increased when Mitomycin is combined with Nelarabine.
Bexarotene The risk or severity of adverse effects can be increased when Bexarotene is combined with Nelarabine.
Vindesine The risk or severity of adverse effects can be increased when Vindesine is combined with Nelarabine.
Floxuridine The risk or severity of adverse effects can be increased when Floxuridine is combined with Nelarabine.
Indomethacin The risk or severity of adverse effects can be increased when Indomethacin is combined with Nelarabine.
Tioguanine The risk or severity of adverse effects can be increased when Tioguanine is combined with Nelarabine.
Vinorelbine The risk or severity of adverse effects can be increased when Vinorelbine is combined with Nelarabine.
Dexrazoxane The risk or severity of adverse effects can be increased when Dexrazoxane is combined with Nelarabine.
Beclomethasone dipropionate The risk or severity of adverse effects can be increased when Beclomethasone dipropionate is combined with Nelarabine.
Sorafenib The risk or severity of adverse effects can be increased when Sorafenib is combined with Nelarabine.
Streptozocin The risk or severity of adverse effects can be increased when Streptozocin is combined with Nelarabine.
Trifluridine The risk or severity of adverse effects can be increased when Trifluridine is combined with Nelarabine.
Gemcitabine The risk or severity of adverse effects can be increased when Gemcitabine is combined with Nelarabine.
Betamethasone The risk or severity of adverse effects can be increased when Betamethasone is combined with Nelarabine.
Teniposide The risk or severity of adverse effects can be increased when Teniposide is combined with Nelarabine.
Epirubicin The risk or severity of adverse effects can be increased when Epirubicin is combined with Nelarabine.
Chloramphenicol The risk or severity of adverse effects can be increased when Chloramphenicol is combined with Nelarabine.
Lenalidomide The risk or severity of adverse effects can be increased when Lenalidomide is combined with Nelarabine.
Altretamine The risk or severity of adverse effects can be increased when Altretamine is combined with Nelarabine.
Zidovudine The risk or severity of adverse effects can be increased when Zidovudine is combined with Nelarabine.
Cisplatin The risk or severity of adverse effects can be increased when Cisplatin is combined with Nelarabine.
Oxaliplatin The risk or severity of adverse effects can be increased when Oxaliplatin is combined with Nelarabine.
Cyclophosphamide The risk or severity of adverse effects can be increased when Cyclophosphamide is combined with Nelarabine.
Vincristine The risk or severity of adverse effects can be increased when Vincristine is combined with Nelarabine.
Fluorouracil The risk or severity of adverse effects can be increased when Fluorouracil is combined with Nelarabine.
Propylthiouracil The risk or severity of adverse effects can be increased when Propylthiouracil is combined with Nelarabine.
Methotrexate The risk or severity of adverse effects can be increased when Nelarabine is combined with Methotrexate.
Carbamazepine The risk or severity of adverse effects can be increased when Carbamazepine is combined with Nelarabine.
Vinblastine The risk or severity of adverse effects can be increased when Vinblastine is combined with Nelarabine.
Fluticasone propionate The risk or severity of adverse effects can be increased when Fluticasone propionate is combined with Nelarabine.
Fluocinolone acetonide The risk or severity of adverse effects can be increased when Fluocinolone acetonide is combined with Nelarabine.
Linezolid The risk or severity of adverse effects can be increased when Linezolid is combined with Nelarabine.
Imatinib The risk or severity of adverse effects can be increased when Imatinib is combined with Nelarabine.
Triamcinolone The risk or severity of adverse effects can be increased when Triamcinolone is combined with Nelarabine.
Clofarabine The risk or severity of adverse effects can be increased when Clofarabine is combined with Nelarabine.
Prednisone The risk or severity of adverse effects can be increased when Prednisone is combined with Nelarabine.
Pemetrexed The risk or severity of adverse effects can be increased when Pemetrexed is combined with Nelarabine.
Fludrocortisone The risk or severity of adverse effects can be increased when Fludrocortisone is combined with Nelarabine.
Mycophenolate mofetil The risk or severity of adverse effects can be increased when Mycophenolate mofetil is combined with Nelarabine.
Daunorubicin The risk or severity of adverse effects can be increased when Daunorubicin is combined with Nelarabine.
Irinotecan The risk or severity of adverse effects can be increased when Irinotecan is combined with Nelarabine.
Methimazole The risk or severity of adverse effects can be increased when Methimazole is combined with Nelarabine.
Etoposide The risk or severity of adverse effects can be increased when Etoposide is combined with Nelarabine.
Sulfasalazine The risk or severity of adverse effects can be increased when Sulfasalazine is combined with Nelarabine.
Dacarbazine The risk or severity of adverse effects can be increased when Dacarbazine is combined with Nelarabine.
Temozolomide The risk or severity of adverse effects can be increased when Temozolomide is combined with Nelarabine.
Penicillamine The risk or severity of adverse effects can be increased when Penicillamine is combined with Nelarabine.
Prednisolone The risk or severity of adverse effects can be increased when Prednisolone is combined with Nelarabine.
Sirolimus The risk or severity of adverse effects can be increased when Sirolimus is combined with Nelarabine.
Mechlorethamine The risk or severity of adverse effects can be increased when Mechlorethamine is combined with Nelarabine.
Azacitidine The risk or severity of adverse effects can be increased when Azacitidine is combined with Nelarabine.
Carboplatin The risk or severity of adverse effects can be increased when Carboplatin is combined with Nelarabine.
Methylprednisolone The risk or severity of adverse effects can be increased when Methylprednisolone is combined with Nelarabine.
Dactinomycin The risk or severity of adverse effects can be increased when Dactinomycin is combined with Nelarabine.
Cytarabine The risk or severity of adverse effects can be increased when Nelarabine is combined with Cytarabine.
Azathioprine The risk or severity of adverse effects can be increased when Azathioprine is combined with Nelarabine.
Doxorubicin The risk or severity of adverse effects can be increased when Doxorubicin is combined with Nelarabine.
Hydroxyurea The risk or severity of adverse effects can be increased when Hydroxyurea is combined with Nelarabine.
Busulfan The risk or severity of adverse effects can be increased when Busulfan is combined with Nelarabine.
Mycophenolic acid The risk or severity of adverse effects can be increased when Mycophenolic acid is combined with Nelarabine.
Topotecan The risk or severity of adverse effects can be increased when Topotecan is combined with Nelarabine.
Mercaptopurine The risk or severity of adverse effects can be increased when Mercaptopurine is combined with Nelarabine.
Thalidomide The risk or severity of adverse effects can be increased when Thalidomide is combined with Nelarabine.
Melphalan The risk or severity of adverse effects can be increased when Melphalan is combined with Nelarabine.

Target Protein

DNA
DNA polymerase alpha catalytic subunit POLA1
DNA ligase 1 LIG1
DNA primase small subunit PRIM1
Ribonucleoside-diphosphate reductase large subunit RRM1

Referensi & Sumber

Artikel (PubMed)
  • PMID: 18035189
    Buie LW, Epstein SS, Lindley CM: Nelarabine: a novel purine antimetabolite antineoplastic agent. Clin Ther. 2007 Sep;29(9):1887-99.
  • PMID: 19825456
    DeAngelo DJ: Nelarabine for the treatment of patients with relapsed or refractory T-cell acute lymphoblastic leukemia or lymphoblastic lymphoma. Hematol Oncol Clin North Am. 2009 Oct;23(5):1121-35, vii-viii. doi: 10.1016/j.hoc.2009.07.008.
  • PMID: 16922610
    Roecker AM, Allison JC, Kisor DF: Nelarabine: efficacy in the treatment of clinical malignancies. Future Oncol. 2006 Aug;2(4):441-8.
  • PMID: 18318562
    Sanford M, Lyseng-Williamson KA: Nelarabine. Drugs. 2008;68(4):439-47.
  • PMID: 20616909
    Reilly KM, Kisor DF: Profile of nelarabine: use in the treatment of T-cell acute lymphoblastic leukemia. Onco Targets Ther. 2009 Feb 18;2:219-28.
  • PMID: 18516261
    Cooper TM: Role of nelarabine in the treatment of T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma. Ther Clin Risk Manag. 2007 Dec;3(6):1135-41.
  • PMID: 18473971
    Curbo S, Karlsson A: Nelarabine: a new purine analog in the treatment of hematologic malignancies. Rev Recent Clin Trials. 2006 Sep;1(3):185-92.
  • PMID: 19157550
    Sigalas P, Tourvas AD, Moulakakis A, Pangalis G, Kontopidou F: Nelarabine induced complete remission in an adult with refractory T-lineage acute lymphoblastic leukemia: A case report and review of the literature. Leuk Res. 2009 Jul;33(7):e61-3. doi: 10.1016/j.leukres.2008.12.005. Epub 2009 Jan 21.
Menampilkan 8 dari 12 artikel.

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