2010/12/12

Atriance



Release form, composition and packing

Infusion solution is transparent, colorless, without any visible mechanical inclusions.

1 ml 1 vial. - Nelarabin 5 mg 250 mg

Excipients: sodium chloride, hydrochloric acid, sodium hydroxide, water, d / and.

Clinico-pharmacological group

Antitumor drug. Antimetabolite.

Pharmacological action

Antitumor drug. Antimetabolite. Nelarabin is a prodrug 9-β-D-arabinofuranozilguanina (ara-G), an analogue of deoxyguanosine. Under the action of adenosine deaminase nelarabin quickly transformed into Ara-G, and then, as a result of phosphorylation produced its 5-monophosphate and further - ara-guanosine triphosphate (ara-GTP). As a result of accumulation of ara-GTP in the blast cells in leukemia, he concurrently embedded in the DNA chain, causing inhibition of DNA synthesis and consequently cell death. In vitro it was shown that T-cells are more sensitive to cytotoxic effects nelarabina compared with B cells.

Pharmacokinetics

Suction

Cmax ara-G plasma levels achieved at the end of infusion nelarabina and on average, higher than the Cmax nelarabina, which involves rapid and intense transformation of the prodrug in medicine. After a two-hour infusion at a dose of nelarabina 1500 mg/m2 adult patients with average Cmax nelarabina and ara-G were 13.9 micromol and 115 micromol, respectively.

AUC nelarabina and ara-G were 5.13 mmol / h and 571 mmol / h, respectively, after infusion of 1500 mg/m2. Cmax for intracellular ara-GTP is achieved through a 3-25 h on the first day of a course of treatment. Mean values of intracellular Cmax and AUC of ara-GTP of 95.6 mmol and 2214 mmol / h for a given dose.

Distribution

Nelarabin and ara-G are characterized by a large Vd. Vd at steady state in adults and children were, respectively, 115 l / m 2 and 89.4 l / m 2. The apparent Vd ara-G is 44.8 l / m 2 and 32.1 l / m 2 in adults and children, respectively.

Linking nelarabina and ara-G to plasma proteins and only slightly less than 25% for both components it does not depend on the concentration in the range up to 600 micromoles. There was no accumulation of any nelarabina nor ara-G, including with the introduction of the scheme-1, 3, 5 day ".

Intracellular concentrations of ara-GTP in lymphoblasts were determined over a long period after the infusion nelarabina. Marked accumulation ara-GTP in the cells after repeated infusions nelarabina scheme "1, 3, 5, with increasing values of Cmax and AUC (0-t) on the third day of treatment by 50% and 30%, respectively, compared with similar indicators for first day of the course.

Metabolism

The main route of biotransformation nelarabina is O-demethylation of adenosine deaminase to form ara-G, further metabolized to guanine. In addition, nelarabin partially hydrolyzed to methylguanine, which then undergoes O-demethylation with the formation of guanine. At the next stage, N-deamination of guanine to form xanthine and its oxidation to uric acid.

Breeding

Nelarabin and ara-G are rapidly cleared from blood plasma, T1 / 2 are, respectively, 30 min and 3 h after infusion at a dose of 1500 mg/m2.

The average clearance nelarabina when administered in doses from 104 to 2900 mg / m 2 in adults and children were, respectively, 138 and 125 l/ch/m2 l/ch/m2 on day 1. The apparent clearance of ara-G is comparable in both age groups and is 9.5 l/ch/m2 adults and 10.8 l/ch/m2 children on day 1.

Nelarabin and ara-G are derived in part by the kidneys. Average number printed by the kidneys is to nelarabina and ara-G, respectively, 5.3% and 23.2% of the administered dose within 24 h after infusion nelarabina on day 1. Renal clearance averaged 16.4 L / h for nelarabina and 4.9 l / h - for ara-G.

Pharmacokinetics in special clinical situations

The main pharmacokinetic parameters in children are similar to those in adults.

No differences in key pharmacokinetic parameters in older patients.

In clinical studies included patients with CC more than 80 ml / min, with impaired renal function Mild (CC 50-80 ml / min) and moderate (creatinine clearance below 50 ml / min) degrees. Mean apparent clearance of ara-G to 7% lower in patients with moderate renal impairment. Differences in efficacy and safety were observed.

For patients with abnormal liver function No data.

Clinical efficacy and safety

Nelarabin demonstrated clinical efficacy at the recommended dose of adult and child patients in two independent clinical studies - CALGB 19801 and COG R9673. In adults with acute T-cell lymphoblastic leukemia or T-cell lymphoma after two or more courses of induction nelarabinom monotherapy resulted in complete remission (PR) in 18% of cases (95% CI: 6-37%) for the duration of complete remission from 15 to 195 + weeks, survival at 1 year was 29%, which confirms the clinical efficacy in this group of patients who had previously conducted an intensive treatment. Close results were obtained in children and patients are not over 21 years old with relapsed or refractory T-cell acute lymphoblastic leukemia or T-cell lymphoma after two or more courses of induction (group 02): monotherapy nelarabinom caused complete remission in 13% (95% CI : 4-27%) for the duration of PR from 4.7 to 36.4 weeks, survival at 1 year was 14%.

In some patients, after two or more ineffective courses of induction, during the period reached on monotherapy nelarabinom complete remission was transplanted blood stem cells. At the time of transplantation duration of complete remission was 1.6-9.3 weeks in children and 6.3-195.4 + weeks in adults. The study PGAA2001 data recovery hematological parameters were obtained from 21 of the 27 patients who after treatment nelarabinom performed transplantation of hematopoietic stem cells. Of these, 20 patients (95%) was confirmed by recovery in neutrophils. The study PGAA2002 data recovery hematological parameters were obtained in 6 of 7 patients who, after therapy nelarabinom performed transplantation of hematopoietic stem cells. In 3 of them (50%) had recovery levels of neutrophils.

In refractory patients, after the inefficient exchange induction therapy nelarabinom secured an impressive rate of complete remission - 18% in adults and children, after two or more previous courses of induction and 44% in children after one year preceding the induction. In addition to the patients who achieved complete remission, one adult patient and in three children with refractory disease achieved complete remission with an optional normalization of hematological parameters.

Indications for use of the drug

Patients with refractory to chemotherapy or relapsed disease:
T-cell acute lymphoblastic leukemia;
T-cell lymphoblastic lymphoma.

Dosing regimen

The course of treatment nelarabinom could only be a specialist with experience in the application of anticancer drugs.

The drug is intended for intravenous infusion in undiluted form.

Adult (16 years and over) the recommended dose of 1500 mg/m2 for 2 h on days 1, 3 and 5 every 21 days.

For children (under 16 years) the recommended dose is 650 mg/m2, iv, for 1 hour, consistently 5 days (days 1-5) every 21 days.

Not enough data to generate specific recommendations to correct dosing regimen in renal impairment (creatinine clearance below 50 ml / min). Given the partial removal of the kidney, requires careful monitoring of clinical condition.

Not enough data to generate specific recommendations to correct dosing regimen for patients with impaired liver function.

Application nelarabina should be discontinued at the first sign of neurotoxicity grade 2 severity or higher on the toxicity criteria of the National Cancer Institute. Increased intervals between dosing may be considered as an alternative for the development of other toxic manifestations, including hematologic toxicity.

Side effect

Safety nelarabina estimated for the general population of patients enrolled in clinical studies. The overall safety assessment was conducted for 103 adults and 84 children enrolled in controlled clinical studies. Most private adverse events: fatigue, gastrointestinal disorders, hematopoietic disorders, disorders of the respiratory system and increase body temperature. Neurotoxicity is dose related.

The incidence of adverse events was classified as follows: very common (≥ 1 / 10), frequently (≥ 1 / 100, <1 / 10), sometimes (≥ 1 / 1000, <1 / 100), rare (≥ 1 / 10 000 , <1 / 1000), very rare (<1 / 10, 000), including individual cases.

Infections and infestations: very often - infections, including sepsis, bacteremia, pneumonia, fungal infections. There are some reports on the development of fatal opportunistic infections. Registered one case of adult progressive multifocal leukoencephalopathy, confirmed by biopsy.