Source: FDA, National Drug Code (US) Revision Year: 2020
L-asparaginase is an enzyme that catalyzes the conversion of the amino acid L-asparagine into aspartic acid and ammonia. The pharmacological effect of ASPARLAS is thought to be based on selective killing of leukemic cells due to depletion of plasma L-asparagine. Leukemic cells with low expression of asparagine synthetase have a reduced ability to synthesize L-asparagine, and therefore depend on an exogenous source of L-asparagine for survival.
Calaspargase pegol-mknl pharmacodynamic (PD) response was assessed through measurement of plasma 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 quantification for more than 18 days following a single dose of ASPARLAS 2,500 U/m2 during the induction phase. Mean CSF asparagine concentrations decreased from a pretreatment concentration of 0.8 µg/mL (N=10) to 0.2 µg/mL on Day 4 (N=37) and remained decreased at 0.2 µg/mL (N=35) 25 days after the administration of a single dose of ASPARLAS 2,500 U/m2 in the induction phase.
Calaspargase pegol-mknl pharmacokinetics (PK) were assessed through measurement of plasma asparaginase 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 3 summarizes 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 of ASPARLAS 2,500 U/m2 in Patients with ALL in Study AALL07P4:
| Parameter | Arithmetic Mean (%CV) N=43 |
|---|---|
| General | |
| Cmax (U/mL) | 1.62 (23.0) |
| AUC0-25day(day∙U/mL) | 16.9 (23.2)* |
| AUC0-∞(day∙U/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 evaluable 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.
The impact of renal and hepatic impairment on the PK of calaspargase pegol-mknl is unknown.
Carcinogenicity, mutagenicity, and impairment of fertility studies have not been conducted with calaspargase pegol-mknl.
The determination of efficacy was based on a demonstration of the achievement and maintenance of nadir serum asparaginase activity (NSAA) above the level of 0.1 U/mL using ASPARLAS 2500 U/m2 intravenously every 3 weeks. The pharmacokinetics of ASPARLAS were studied when used in combination with 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 and 9 (7%) other or unknown. The results showed that 123 (99%, 95% CI: 96%-100%) of the 124 patients maintained NSAA >0.1 U/mL at weeks 6, 12, 18, 24 and 30.
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