Population pharmacokinetics of intramuscular recombinant Erwinia chrysanthemi asparaginase (JZP458) in patients with acute lymphoblastic leukemia.

JZP458 is a recombinant Erwinia chrysanthemi asparaginase for patients with acute lymphoblastic leukemia (ALL)/lymphoblastic lymphoma (LBL) who have developed hypersensitivity to Escherichia coli-derived asparaginases. A population pharmacokinetic (PopPK) model was developed for intramuscular (i.m.) JZP458 using serum asparaginase activity (SAA) data from 166 patients with ALL/LBL enrolled in a phase II/III study conducted in collaboration with the Children's Oncology Group (AALL1931; NCT04145531). The pharmacokinetics of i.m. JZP458 is best characterized by a one-compartment model with mixed-order absorption and linear elimination, with body surface area included as an allometric covariate on JZP458 SAA clearance and volume, and race (i.e., Black/African American) and disease subtype (i.e., T-cell ALL) as covariates on JZP458 SAA clearance. The PopPK model was used to simulate SAA profiles to estimate the likelihood of achieving nadir SAA (NSAA) levels greater than or equal to 0.1 IU/mL with different dosing regimens. Model-based simulations suggest when JZP458 is administered i.m. at 25/25/50 mg/m Monday/Wednesday/Friday (MWF), 92.1% of subjects (95% confidence interval [CI]: 90.9%, 93.3%) are expected to achieve the last 72-h (after 50 mg/m dose) NSAA level greater than or equal to 0.1 IU/mL, and 93.8% (95% CI: 92.7%, 94.9%) are expected to achieve the last 48-h (after 25 mg/m dose) NSAA level greater than or equal to 0.1 IU/mL. When JZP458 is administered 25 mg/m i.m. every 48 h, 93.8% (95% CI: 92.7%, 94.8%) are expected to achieve the last 48-h NSAA level greater than or equal to 0.1 IU/mL. These data supported the i.m. dose of 25 mg/m every 48 h or 25/25/50 mg/m on a MWF dosing schedule in patients with ALL/LBL.