RYLAZE Solution for injection Ref.[109542] Active ingredients: Asparaginase

Asparaginase erwinia chrysanthemi (recombinant)-rywn exposure-response relationships and the time course of pharmacodynamic response are unknown.

The pharmacokinetic parameters of asparaginase erwinia chrysanthemi (recombinant)-rywn are presented based on serum asparaginase activity (SAA) after administration of RYLAZE in pediatric and young adult patients with ALL or LBL, unless otherwise specified. Asparaginase erwinia chrysanthemi (recombinant)-rywn maximum SAA (C_max) and area under the SAA-time curve (AUC) increase proportionally over a dosage range from 12.5 to 50 mg/m² (0.25 to 1 times the maximum approved recommended dose of 50 mg/m²). The simulated exposures for asparaginase erwinia chrysanthemi (recombinant)-rywn after administration of the approved recommended dosages in a virtual population are summarized in Table 4.

Table 4. Simulated RYLAZE Pharmacokinetic Parameters Based on SAA:

^a C_trough at maximum interval of 58 hours after the last 25 mg/m² Wednesday morning dose.
^b C_trough at maximum interval of 67 hours after the last 50 mg/m² Friday afternoon dose.

Absorption

The median (min, max) T_max of asparaginase erwinia chrysanthemi (recombinant)-rywn after intramuscular administration is 12 (8, 24) hours. The mean absolute bioavailability after intramuscular administration is 37% in healthy subjects.

Distribution

The geometric mean (CV) volume of distribution of asparaginase erwinia chrysanthemi (recombinant)-rywn is 1.37 L/m² (47).

Elimination

The geometric mean (CV) clearance of asparaginase erwinia chrysanthemi (recombinant)-rywn is 0.17 L/hour/m² (42) and the apparent half-life is 15.9 (11%) hours.

Metabolism

Asparaginase erwinia chrysanthemi (recombinant)-rywn is expected to be metabolized into small peptides by catabolic pathways.

Specific Populations

There were no clinically significant differences in the pharmacokinetics of asparaginase erwinia chrysanthemi (recombinant)-rywn based on age (1.4 to 25 years), weight (9 to 131 kg), or sex after the dose was adjusted by body surface area (BSA). The effect of renal and hepatic impairment on the pharmacokinetics of asparaginase erwinia chrysanthemi (recombinant)-rywn has not been studied.

Body Surface Area

The volume of distribution and clearance of asparaginase erwinia chrysanthemi (recombinant)-rywn increase with increasing BSA (0.44 to 2.53 m²).

Racial and Ethnic Groups

Black or African American patients had 29% lower clearance which may increase SAA exposure compared to White and Asian patients. There were no clinically significant differences in clearance between Hispanic and Non-Hispanic patients.

Carcinogenicity, mutagenicity, and impairment of fertility studies have not been conducted with asparaginase erwinia chrysanthemi (recombinant)-rywn.

In a fertility and early embryonic development study in rats, asparaginase Erwinia chrysanthemi had no effect on male or female fertility when administered intramuscularly at doses of up to 12 mg/m ² (approximately 0.48 times the maximum recommended human dose) every other day for a total of 35 doses. In males, decreased sperm count was observed at all doses but did not impact fertility.

The efficacy of RYLAZE for the treatment of patients with acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL) who have developed hypersensitivity to E. coli-derived asparaginase as a component of a multi-agent chemotherapeutic regimen was evaluated in Study JZP458-201 (NCT04145531), an open-label, multi-cohort, multi-center trial. In this trial, RYLAZE was administered at various dosages and routes of administration every Monday, Wednesday, and Friday for a total of 6 doses to replace each dose of pegaspargase.

For the 225 evaluable patients, the median age was 10 years (range: 1-25 years); 61% were male and 39% were female; 69% were White, 11% were Black/African American, 4% were Asian, and 16% were of other or unknown race: 187 (83%) patients had experienced a hypersensitivity reaction (Grade ≥ 3) to pegaspargase, and 15 patients (7%) reported silent inactivation.

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 by simulation. Table 5 shows the proportion with NSAA ≥ 0.1 U/mL for each approved dosage regimen based on simulation in a virtual population [see Clinical Pharmacology (12.3)].

Table 5. Proportion (95% CI) with NSAA ≥ 0.1 U/mL by Simulation:

^a Based on 2,000 virtual subjects.
^b Based on maximum interval of 58 hours between the Wednesday morning and Friday afternoon doses.
^c Based on maximum interval of 67 hours between the Friday afternoon and Monday morning doses.