Population Pharmacokinetic Modeling of Intravenous Asparaginase Erwinia Chrysanthemi: Impact of Varied Infusion Rates on Exposure
Authors: Zomorodi Katie , Dumas Todd , Berry Seth , Johnston Curtis , Eller Mark 
Published: October 2019

Abstract
Introduction: Asparaginase Erwinia chrysanthemi (Erwinia), an asparagine-specific enzyme indicated as a component of a multiagent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia (ALL) who have developed hypersensitivity to E coli-derived asparaginase, is approved in the US for intramuscular and intravenous (IV) administration (Erwinaze USPI 2016). IV administration of proteins, such as asparaginase, may be associated with infusion reactions that may be mitigated by prolongation of the infusion time. Pharmacokinetic (PK) simulations based on a population PK (PPK) model were performed to evaluate PK of IV Erwinia infusions over 2 hours vs 1 hour.
Methods: The serum asparaginase activity (SAA) levels from a phase 2, open label, single arm, multicenter, PK study following Erwinia treatment by IV infusion in ALL subjects (1-30 years old) with a previously documented hypersensitivity reaction (≥Grade 2) to pegaspargase were characterized by nonlinear mixed-effects modeling using NONMEM® software. The PPK model included data after 6 doses (1 cycle) of IV Erwinia administered over 1 hour at a 25,000 IU/m2 dose given on a Monday/Wednesday/Friday schedule. The PPK base model for IV Erwinia was identified by comparing different structural and error models. A stepwise approach with forward addition and backward elimination was used to identify important covariates. Visual predictive checks (VPC) were used to demonstrate PPK model predictability. Resampling of the original PK population was used to create a virtual patient population (n = 9999) to simulate average SAA levels and corresponding variability for both 1- and 2-hour IV infusion regimens, summarized by 95% prediction intervals.
Results: The PK analysis set contained 24 subjects with 331 evaluable PK samples collected over 6 cycles of therapy. The majority of PK samples were collected during Cycle 1 (55%) with the majority of subjects being male (62.5%) and Caucasian (79%). The median (range) for age was 6.5 years (1-17) and for weight 21.4 kg (10.9 to 118.3). Trough SAA levels ≥0.1 IU/mL at 48 hours post dose 5 (primary endpoint) were achieved by 83% of the evaluable subjects in Cycle 1 (95% CI: 63%-95%). A 2-compartment model with inter-individual variability on clearance (CL) was found to best describe the PK of Erwinia. The final model for CL was:
CL [mL/hr] = 123[mL/hr] + 17[mL/hr] * (weight [kg] / 21.4 kg)
The central and peripheral volumes of distribution were 1.59 L and 0.154 L, respectively. As more PK samples were available for Cycle 1, separate proportional error models partitioned residual variability for Cycle 1 (36.6%) vs Cycles 2-6 (48.6%). The derived mean half-life estimate (CV%) was 7.51 hours (23.9%). The VPC demonstrated the bulk (>90%) of the observed SAA falling within the 95% PPK model-based simulation prediction intervals. The PPK model-based SAA simulation results after 1- and 2-hour IV infusions are displayed in Table 1 and Figure 1. Despite different initial rates of rise, similar SAA vs time profiles were observed when comparing 1- vs 2-hour infusion durations (Figure 1), with a similar number of subjects achieving therapeutic trough levels ≥ 0.1 IU/mL (Table 1).
Conclusions: The final PPK model demonstrated a good ability to predict SAA allowing estimation of elimination characteristics and the application of subsequent model-based simulations.The PK simulations for 1- vs 2-hour IV Erwinia showed similar mean 48-hour trough SAA levels, as well as similar proportions of subjects having therapeutic 48-hour trough SAA ≥ 0.1 IU/mL. Based on these PK results, duration of IV Erwinia could be increased from 1 to 2 hours, which may reduce symptoms of infusion reactions. Reducing infusion reactions may potentially enablemore patients to complete Erwinia treatment. Upon approval from FDA in 2016, IV infusion duration in the Erwinaze USPI was revised from 1 hour to 1-2 hours; this is also consistent with the updated Children's Oncology Group protocols.
Support: Jazz Pharmaceuticals.

Disclosures
Zomorodi: Jazz Pharmaceuticals: Employment, Equity Ownership. Dumas:Quintiles: Employment; Jazz Pharmaceuticals: Consultancy. Berry:Quintiles: Employment; Jazz Pharmaceuticals: Consultancy. Johnston:Jazz Pharmaceuticals: Consultancy; Quintiles: Employment. Eller:Jazz Pharmaceuticals: Employment, Equity Ownership.