Title: Models of Asparaginase and Asparagine Pharmacokinetics and Pharmacodynamics in Pediatric Acute Lymphoblastic Leukemia

Objectives: Asparaginase (ASP) is an anticancer drug which is especially important for acute lymphoblastic leukemia (ALL) [1-9]. It’s mechanism of action is to reduce levels of asparagine by hydrolyzing it to aspartic acid and ammonia. Since leukemic cells do not synthesize adequate asparagine, they rely on serum asparagine for protein synthesis. Therefore, ASP selectively starves leukemia cells. There are currently three preparations of ASP available: E-coli (Elspar); PEG (Oncospar); and Erwinia (Erwinase). The goal of this study is to assess the pharmacokinetics and pharmacodynamics of ASP using both descriptive and mechanistic models. Methods: A cohort of 38 patients enrolled on St. Jude R16 protocol for relapsed ALL was used in this study. Patients were randomly assigned to receive either Elspar (10,000 IU/m2, thrice weekly for 12 doses over 26 days) or Oncospar (2,500 IU/m2 weekly for 4 doses over 21 days) during induction therapy. Five patients who had a hypersensitivity reaction to these preparations were switched to Erwinase. ASP pharmacokinetic samples were collected on days 8 and 29 of induction therapy. Additionally, serial plasma and CSF asparagine samples, serum samples for anti-ASP antibodies, and toxicity data (hypersensitivity to ASP) were collected over the 29 day treatment period. A mechanistic pharmacokinetic/pharmacodynamic model was developed which describes the plasma disposition of ASP and the enzymatic reaction between ASP and asparagine, including the endogenous formation of asparagine. This model was used to quantitatively describe the current data set, and to simulate th