he pharmacological effect of ASPARLAS is thought to be based on selectivekilling of leukemic cells due to depletion of plasma L-asparagine. Leukemic cells with low expression ofasparagine synthetase have a reduced ability to synthesize L-asparagine, and therefore depend on anexogenous source of L-asparagine for survival.
12.2 Pharmacodynamics
Calaspargase pegol-mknl pharmacodynamic (PD) response was assessed through measurement ofplasma and cerebrospinal fluid (CSF) asparagine concentrations via an LC-MS/MS assay.
Asparagine concentrations in plasma (N=41) were maintained below the assay limit of quantificationfor more than 18 days following a single dose of ASPARLAS 2,500 U/m2 during the induction phase.
MeanCSF asparagine concentrations decreased from a pretreatment concentration of 0.8 µg/mL (N=10) to0.2 µg/mL on Day 4 (N=37) and remained decreased at 0.2 µg/mL (N=35) 25 days after the administrationof a single dose of ASPARLAS 2,500 U/m2 in the induction phase.
12.3 Pharmacokinetics
Calaspargase pegol-mknl pharmacokinetics (PK) were assessed through measurement of plasmaasparaginase activity via a coupled enzymatic assay.
The plasma asparaginase activity pharmacokinetics were characterized in 43 patients (1 to 26 years)with newly diagnosed high risk B-precursor ALL treated with a multidrug backbone therapy.
Table 3summarizes the plasma asparaginase activity pharmacokinetic parameters after a single dose of
ASPARLAS 2,500 U/m2 in the induction phase.
Table 3: Plasma Asparaginase Activity Pharmacokinetic Parameters After a Single Dose ofASPARLAS 2,500 U/m2 in Patients with ALL in Study AALL07P4Parameter Arithmetic Mean (%CV)
N=43
General
Cmax (U/mL) 1.62 (23.0)
AUC0-25day (dayU/mL) 16.9 (23.2)*
AUC0–∞ (dayU/mL)† 25.5 (30.4)*
Absorption
Tmax (h)† 1.17 (1.05, 5.47)‡
Distribution
Vss (L) 2.96 (84.3)*
Elimination
t1/2 (day)§ 16.1 (51.9)*
Clearance (L/day) 0.147 (76.1)*
* N= 42 eva luable subjects.
† Tmax generally near end of a 1 hour calaspargase pegol-mknl intravenous (IV) infusion.
‡ Median (10th, 90th percentiles).
§ Plasma asparaginase activity pharmacokinetics are nonlinear following ASPARLAS administration.
Specific Populations
The impact of renal and hepatic impairment on the PK of calaspargase pegol-mknl is unknown.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity, mutagenicity, and impairment of fertility studies have not been conducted withcalaspargase pegol-mknl.
14 CLINICAL STUDIES
14.1 Acute Lymphoblastic Leukemia (ALL)
The determination of efficacy was based on a demonstration of the achievement and maintenanceof nadir serum asparaginase activity (NSAA) above the level of 0.1 U/mL using ASPARLAS 2500 U/m2intravenously every 3 weeks. The pharmacokinetics of ASPARLAS were studied when used in combinationwith multiagent chemotherapy in 124 patients with B cell lineage acute lymphoblastic leukemia (ALL).
Among these patients, the median age was 11.5 years (range 1 – 26); 62 (50%) were male, 102 (82%)white, 6 (5%) Asian, 5 (4%) Black or African American, 2 (2%) Native Hawaiian or Pacific Islander and9 (7%) other or unknown. The results showed that 123 (99%, 95% CI: 96% - 100%) of the 124 patientsmaintained NSAA > 0.1 U/mL at weeks 6, 12 |
