Population Pharmacokinetic Model Development and Simulation for Recombinant Erwinia Asparaginase Produced in Pseudomonas fluorescens (JZP‐458)

JZP‐458 is a recombinant Erwinia asparaginase produced using a novel Pseudomonas fluorescens expression platform that yields an enzyme expected to lack immunologic cross‐reactivity to Escherichia coli–derived asparaginases. It is being developed as part of a multiagent chemotherapeutic regimen to treat acute lymphoblastic leukemia or lymphoblastic lymphoma patients who develop E coli–derived asparaginase hypersensitivity. A population pharmacokinetic (PopPK) model was developed for JZP‐458 using serum asparaginase activity (SAA) data from a phase 1, single‐dose study (JZP458‐101) in healthy adults. Effects of intrinsic covariates (body weight, body surface area, age, sex, and race) on JZP‐458 PK were evaluated. The model included SAA data from 24 healthy adult participants from the phase 1 study who received JZP‐458: intramuscular (IM) data at 12.5 mg/m(2) (N = 6) and 25 mg/m(2) (N = 6), and intravenous (IV) data at 25 mg/m(2) (N = 6) and 37.5 mg/m(2) (N = 6). Model simulations of adult and pediatric SAA profiles were performed to explore the likelihood of achieving a therapeutic target nadir SAA (NSAA) level ≥0.1 IU/mL based on different administration strategies. PopPK modeling and simulation suggest JZP‐458 is expected to achieve 72‐hour NSAA levels ≥0.1 IU/mL in 100% of adult or pediatric populations receiving IM administration at 25 mg/m(2), and in 80.9% of adult and 94.5% of pediatric populations receiving IV administration at 37.5 mg/m(2) on a Monday/Wednesday/Friday (M/W/F) dosing schedule. Based on these results, the recommended starting dose for the phase 2/3 pivotal study is 25 mg/m(2) IM or 37.5 mg/m(2) IV on a M/W/F dosing schedule in pediatric and adult patients.