Nelarabine

297.27

297.27

1806241-263-5

60158CV180

755985

DTXSID6046842

C1704

L01BB07|L - Antineoplastic and immunomodulating agents

149

-0.7

1.98±0.1 g/cm3(Predicted)

208-210 °C @ Solvent: Methanol

721.0±70.0 °C(Predicted)

389.9±35.7 °C

1.829

Slightly soluble to soluble in water

D20 +55.9° (c = 0.27 in DMF)

P201, P202, P260, P264, P270, P273, P281, P308+P313, P314, P405, P501

H341

|Danger|H341 (75%): Suspected of causing genetic defects [Warning Germ cell mutagenicity]|P201, P202, P260, P264, P270, P273, P281, P308+P313, P314, P405, and P501|Aggregated GHS information provided by 4 companies from 4 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

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.

In clinical trials, serum enzymes elevations occurred in a small proportion of patients treated with nelarabine when given as sole therapy for refractory or relapsed acute leukemia. These elevations are generally mild-to-moderate, transient and asymptomatic. Elevations of aminotransferase levels above 5 times the upper limit of normal are reported in 4% of patients with leukemia receiving nelarabine. The elevations rarely require dose adjustment or delay in therapy. Cases of clinically apparent liver injury due to nelarabine have been reported to occur, but few details are available. A single case report of clinically apparent liver injury attributed to nelarabine has been published with rapid onset of jaundice during a second course of nelarabine, a hepatocellular pattern of enzyme elevations, no immunoallergic or autoimmune features and a rapid improvement upon stopping.

Nelarabine and ara-G are not substantially bound to human plasma proteins (<25%) in vitro, and binding is independent of nelarabine or ara-G concentrations up to 600 mM.

For the treatment of pediatric and adult patients with acute T-cell lymphoblastic leukemia and T-cell lymphoblastic lymphoma whose disease has not responded to or has relapsed following treatment with at least two chemotherapy regimens.|FDA Label|Nelarabine is indicated for the treatment of patients with T-cell acute lymphoblastic leukaemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) whose disease has not responded to or has relapsed following treatment with at least two chemotherapy regimens.Due to the small patient populations in these disease settings, the information to support theseindications is based on limited data.|Drug: Nelarabine

Nelarabine is a purine analogue and antineoplastic agent used in the therapy of T cell lymphoblastic leukemia or lymphoma. Nelarabine is associated with a low rate of transient serum enzyme elevations during therapy and has been linked to rare instances of clinically apparent acute liver injury with jaundice.

Antineoplastic Agents

Nelarabine is a prodrug of the cytotoxic deoxyguanosine analogue 9-ß-D-arabinofuranosylguanine (ara-G). Nelarabine is demethylated by adenosine deaminase (ADA) to ara-G. Ara-G is then transported into cells, where it undergoes three phosphorylation steps, resulting in the formation of ara-G triphosphate (ara-GTP). In the first phosphorylation step, ara-G is converted to ara-G monophosphate (ara-GMP). Ara-GMP is then monophosphorylated by deoxyguanosine kinase and deoxycytidine kinase to ara-G diphosphate, and then subsequently to the active ara-G triphosphate (ara-GTP). Ara-GTP is the one that exerts the pharmacological effect. Pre-clinical studies have demonstrated that targeted T-cells possess marked sensitivity to the agent.

Excretion: Nelarabine and ara-G are partially eliminated by the kidneys.|197  +/-  189 L/h/m2 [Adult patients with refractory leukemia or lymphoma receiving doses of 199 to 2,900 mg/m2]

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. Ring opening of uric acid followed by further oxidation results in the formation of allantoin.

Nelarabine and ara-G are rapidly eliminated from plasma with a half-life of approximately 30 minutes and 3 hours.

Once nelarabine is metabolized into ara-GTP, the metabolite accumulates in leukemic blasts and incorporates into DNA to exert its S phase-specific cytotoxic effects, leading to the induction of fragmentation and apoptosis. Ara-GTP competes with endogenous deoxyGTP (dGTP) for incorporation into DNA. Once ara-GTP is incorporated at the 3' end of DNA, further DNA elongation is inhibited, which signals apoptosis and leads to cellular destruction. Additional cytotoxic activities may exist, but these are not fully understood.

2-amino-6-methoxypurine arabinoside

Human drugs -> Atriance -> EMA Drug Category|Antineoplastic agents -> Human pharmacotherapeutic group|Human drugs -> Rare disease (orphan)|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients