Arranon (Page 4 of 5)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Nelarabine is a prodrug of the deoxyguanosine analogue 9-β-D -arabinofuranosylguanine (ara-G), a nucleoside metabolic inhibitor. Nelarabine is demethylated by 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.

12.3 Pharmacokinetics

Absorption: 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 1500 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 1500 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 1500 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 1500 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). Because the intracellular levels of ara-GTP were so prolonged, its elimination half-life could not be accurately estimated.

Distribution: 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.

Metabolism: The principal route of metabolism for nelarabine is O-demethylation by ADA 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.

Excretion: 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 I pharmacokinetic data at nelarabine doses of 199 to 2900 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.

Pediatrics: No pharmacokinetic data are available in pediatric patients at the once-daily 650 mg/m2 nelarabine dosage. Combined Phase I pharmacokinetic data at nelarabine doses of 104 to 2900 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 2 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 (8.5)].

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% to 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 I trials, patients were categorized into 3 groups: normal with CLCr greater than 80 mL/min (n = 67), mild with CLCr = 50 to 80 mL/min (n = 15), and moderate with CLCr less than 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 in Specific Populations (8.6), Dosage and Administration (2.3)]. 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 (8.7)].

Drug Interactions: Cytochrome P450: Nelarabine and ara-G did not significantly inhibit 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 1200-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 ADA. Inhibition of ADA may result in a reduction in the conversion of the prodrug 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 (7)].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity testing of nelarabine has not been done. However, nelarabine was mutagenic when tested in vitro in L5178Y/TK mouse lymphoma cells with and without metabolic activation. No studies have been conducted in animals to assess genotoxic potential or effects on fertility. The effect on human fertility is unknown.

14 CLINICAL STUDIES

14.1 Adult Clinical Trial in Relapsed or Refractory T-ALL and T-LBL

The safety and efficacy of ARRANON in adult patients were studied in a clinical trial which included 39 treated patients, 28 who had T-ALL or T-LBL that had relapsed following or was refractory to at least two prior induction regimens. A 1500-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 to 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 trial 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 trial 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 With 1500 mg/m2 of ARRANON Administered Intravenously Over 2 Hours on Days 1, 3, and 5 Repeated Every 21 Days
Abbreviations: CR, complete response; CI, confidence interval;CR*, complete response without hematologic recovery.a Does not include 1 patient who was transplanted (duration of response was 156+ weeks).
N = 28
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]

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.

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