fused over 2 hours in adult patients. Exposure to ara-G (AUC) 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 were obtained for nelarabine between Days 1 and 5 at the proposed nelarabine adult dosage of 1,500 mg/m2, indicating that the pharmacokinetics of nelarabine after multiple-dosing are predictable from single dosing. There are not enough data for ara-G to make a comparison between Day 1 and Day 5. After a nelarabine adult dosage of 1,500 mg/m2, a mean 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 half-life could not be accurately estimated.
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. Specifically, for nelarabine, VSS values were 197 ± 216 L/m2 and 213 ± 358 L/m2 in adult and pediatric patients, respectively. For ara-G, VSS/F values were 50 ± 24 L/m2 and 33 ± 9.3 L/m2 in adult and pediatric patients, respectively.
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 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.
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.
Special Populations
Gender: Gender has no effect on nelarabine or ara-G pharmacokinetics.
Race: Most patients enrolled in Phase 1 studies were Whites. In general, nelarabine mean clearan
