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Mechanism of Action
Nelarabine is a pro-drug of the deoxyguanosine analogue 9-β-D-arabinofuranosylguanine (ara-G), a nucleoside metabolic inhibitor. Nelarabine is demethylated by adenosine deaminase (ADA) to ara-G, mono-phosphorylated by deoxyguanosine kinase and deoxycytidine kinase, and subsequently converted to the active 5'-triphosphate, ara-GTP. Accumulation of ara-GTP in leukemic blasts allows for incorporation into deoxyribonucleic acid (DNA), leading to inhibition of DNA synthesis and cell death. Other mechanisms may contribute to the cytotoxic and systemic toxicity of nelarabine.
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 μg/mL and 31.4 ± 5.6 μg/mL, respectively, after a 1,500 mg/m² nelarabine dose infused over 2 hours in adult patients. 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 μg.h/mL versus 4.4 ± 2.2 μg.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. After a nelarabine adult dose of 1,500 mg/m , 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 μg.h/mL versus 4.4 ± 2.2 μg.h/mL and 162 ± 49 μg.h/mL, respectively). Because the intracellular levels of ara-GTP were so prolonged, its elimination halflife could not be accurately estimated.
Nelarabine and ara-G are extensively distributed throughout the body. For nelarabine, Vss values were 197 ± 216 L/m² in adult patients. For ara-G, Vss/F values were 50 ± 24 L/m² in adult patients.
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 μM.
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.
Nelarabine and ara-G are partially eliminated by the kidneys. 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. 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 1 pharmacokinetic data at nelarabine doses of 199 to 2,900 mg/m² (n = 66 adult patients) indicate that the mean clearance (CL) of nelarabine is 197 ± 189 L/h/m² on Day 1. The apparent clearance of ara-G (CL/F) is 10.5 ± 4.5 L/h/m² on Day 1. 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.
No pharmacokinetic data are available in pediatric patients at the once daily 650 mg/m² nelarabine dosage. Combined Phase 1 pharmacokinetic data at nelarabine doses of 104 to 2,900 mg/m² indicate that the mean clearance (CL) of nelarabine is about 30% higher in pediatric patients than in adult patients (259 ± 409 L/h/m² versus 197 ± 189 L/h/m² , respectively) (n = 66 adults, n = 22 pediatric patients) on Day 1. The apparent clearance of ara-G (CL/F) is comparable between the two groups (10.5 ± 4.5 L/h/m² in adult patients and 11.3 ± 4.2 L/h/m² in pediatric patients) on Day 1. Nelarabine and ara-G are extensively distributed throughout the body. For nelarabine, Vss values were 213 ± 358 L/m² in pediatric patients. For ara-G,Vss/F values were 33 ± 9.3 L/m² in pediatric patients. Nelarabine and ara-G are rapidly eliminated from plasma in pediatric patients, with a half-life of 13 minutes and 2 hours, respectively.
Effect of Age
Age has no effect on the pharmacokinetics of nelarabine or ara-G in adults. Decreased renal function, which is more common in the elderly, may reduce ara-G clearance [see Use in Specific Populations].
Effect of Gender
Gender has no effect on nelarabine or ara-G pharmacokinetics.
Effect of Race
In general, nelarabine mean clearance and volume of distribution values tend to be higher in Whites (n = 63) than in Blacks (by about 10%) (n = 15). The opposite is true for ara-G; mean apparent clearance and volume of distribution values tend to be lower in Whites than in Blacks (by about 15-20%). No differences in safety or effectiveness were observed between these groups.
Effect of Renal Impairment
The pharmacokinetics of nelarabine and ara-G have not been specifically studied in renally impaired or hemodialyzed patients. Nelarabine is excreted by the kidney to a small extent (5 to 10% of the administered dose). Ara-G is excreted by the kidney to a greater extent (20 to 30% of the administered nelarabine dose). In the combined Phase 1 studies, patients were categorized into 3 groups: normal with CLcr > 80 mL/min (n = 67), mild with CLcr= 50-80 mL/min (n = 15), and moderate with CLcr < 50 mL/min (n = 3). The mean apparent clearance (CL/F) of ara-G was about 15% and 40% lower in patients with mild and moderate renal impairment, respectively, than in patients with normal renal function [see Use inSpecific Populations and DOSAGE AND ADMINISTRATION]. No differences in safety or effectiveness were observed.
Effect of Hepatic Impairment
The influence of hepatic impairment on the pharmacokinetics of nelarabine has not been evaluated [see Use in Specific Populations].
Cytochrome P450: Nelarabine and ara-G did not significantlyinhibit the activities of the human hepatic cytochrome P450 isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4 in vitro at concentrations of nelarabine and ara-G up to 100 μM.
Fludarabine: Administration of fludarabine 30 mg/m² as a 30-minute infusion 4 hours before a 1,200 mg/m² infusion of nelarabine did not affect the pharmacokinetics of nelarabine, ara-G, or ara-GTP in 12 patients with refractory leukemia.
Pentostatin: There is in vitro evidence that pentostatin is a strong inhibitor of adenosine deaminase. Inhibition of adenosine deaminase may result in a reduction in the conversion of the pro-drug nelarabine to its active moiety and consequently in a reduction in efficacy of nelarabine and/or change in adverse reaction profile of either drug [see DRUG INTERACTIONS].
The safety and efficacy of ARRANON were evaluated in two open-label, single-arm, multicenter studies.
Adult Clinical Study
The safety and efficacy of ARRANON in adult patients were studied in a clinical trial which included 39 treated patients, 28 who had T-cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic lymphoma (T-LBL) that had relapsed following or was refractory to at least two prior induction regimens. A 1,500 mg/m² dose of ARRANON was administered intravenously over 2 hours on days 1, 3, and 5 repeated every 21 days. Patients who experienced signs or symptoms of grade 2 or greater neurologic toxicity on therapy were to be discontinued from further therapy with ARRANON. Seventeen patients had a diagnosis of T-ALL and 11 had a diagnosis of T-LBL. For patients with > 2 prior inductions, the age range was 16-65 years(mean 34 years) and most patients were male (82%) and Caucasian (61%). Patients with central nervous system (CNs) disease were not eligible.
Complete response (CR) in this study was defined as bone marrow blast counts < 5%, no other evidence of disease, and full recovery of peripheral blood counts. Complete response without complete hematologic recovery (CR*) was also assessed. The results of the study for patients who had received > 2 prior inductions are shown in Table 5.
Table 5: Efficacy Results in
Adult Patients With > 2 Prior Inductions Treated with1,500 mg/m of ARRANON
Administered Intravenously Over 2 Hours on Days 1, 3, and 5Repeated Every 21
|CR plus CR* % (n) [95% CI]||21% (6) [8%, 41%]|
|CR % (n) [95% CI]||18% (5) [6%, 37%]|
|CR* % (n) [95% CI]||4% (1) [0%, 18%]|
|Duration of CR plus CR* (range in weeks)a||4 to 195+|
|Median overall survival (weeks) [95% CI]||20.6 weeks [10.4, 36.4]|
|CR = Complete response
CR* = Complete response without hematologic recovery
a Does not include 1 patient who was transplanted (duration of response was 156+ weeks).
The mean number of days on therapy was 56 days (range of 10 to 136 days). Time to CR plus CR* ranged from 2.9 to 11.7 weeks.
Pediatric Clinical Study
The safety and efficacy of ARRANON in pediatric patients were studied in a clinical trial which included patients 21 years of age and younger, who had relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic lymphoma (T-LBL). Eighty-four (84) patients, 39 of whom had received two or more prior induction regimens, were treated with 650 mg/m² /day of ARRANON administered intravenously over 1 hour daily for 5 consecutive days repeated every 21 days (see Table 6). Patients who experienced signs or symptoms of grade 2 or greater neurologic toxicity on therapy were to be discontinued from further therapy with ARRANON.
Table 6: Pediatric Clinical Study - Patient Allocation Patient
|Patients treated at 650 mg/m /day x 5 days every 21 days.||84|
|Patients with T-ALL or T-LBL with two or more prior induction treated at 650 mg/m²/day x 5 days every 21 days.||39|
|Patients with T-ALL or T-LBL with one prior induction treated at 650 mg/m²/day x 5 days every 21 days.||31|
The 84 patients ranged in age from 2.5-21.7 years (overall mean, 11.9 years), 52% were 3 to 12 years of age and most were male (74%) and Caucasian (62%). The majority (77%) of patients had a diagnosis of T-ALL.
Complete response (CR) in this study was defined as bone marrow blast counts < 5%, no other evidence of disease, and full recovery of peripheral blood counts. Complete response without full hematologic recovery (CR*) was also assessed as a meaningful outcome in this heavily pretreated population. Duration of response is reported from date of response to date of relapse, and may include subsequent stem cell transplant. Efficacy results are presented in Table 7.
Table 7: Efficacy Results in Patients 21 Years of Age and
Younger at Diagnosis With > 2 Prior Inductions Treated with 650 mg/m of
ARRANON Administered Intravenously Over 1 Hour Daily for 5 Consecutive Days
Repeated Every 21 Days
|CR plus CR* % (n) [95% CI]||23% (9) [11%, 39%]|
|CR % (n) [95% CI]||13% (5) [4%, 27%]|
|CR* % (n) [95% CI]||10% (4) [3%, 24%]|
|Duration of CR plus CR* (range in weeks)a||3.3 to 9.3|
|Median overall survival (weeks) [95% CI]||13.1 [8.7, 17.4]|
|CR = Complete response
CR* = Complete response without hematologic recovery
a Does not include 5 patients who were transplanted or had subsequent systemic chemotherapy (duration of response in these 5 patients was 4.7 to 42.1 weeks).
The mean number of days on therapy was 46 days (range of 7 to 129 days). Median time to CR plus CR* was 3.4 weeks (95% CI: 3.0, 3.7).
Last reviewed on RxList: 2/15/2012
This monograph has been modified to include the generic and brand name in many instances.
Additional Arranon Information
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