Submitted July 13, 2006
Accepted November 20, 2006
Pharmacodynamics and safety of intravenous pegaspargase during remission induction in adults 55 years old or younger with newly diagnosed acute lymphoblastic leukemia
Dan Douer*, Henry Yampolsky, Lewis J Cohen, Kristy Watkins, Alexandra M Levine, Antonia P Periclou, and Vassilios I Avramis
Division of Hematology, Dept of Medicine, University of Southern California & Norris Comprehensive Cancer Center, Los Angeles, CA
Childrens Hospital Los Angeles, University of Southern California & Norris Comprehensive Cancer Center, Los Angeles, CA
* Corresponding author; email: douer_d{at}ccnt.hsc.usc.edu.
In contrast to that in children, pharmacokinetic, pharmacodynamic and safety information on pegaspargase in adults is very limited. We administered a single intravenous dose of pegaspargase (2000 IU/m2) as part of a standard front-line induction regimen to 25 adults, with newly diagnosed ALL, and obtained serum samples on several time points. The population mean peak serum concentration of asparaginase enzymatic activity was 1 IU/ml, the elimination half-life was 7 days and the volume of distribution was 2.43 L/m2. After the single dose, asparagine deamination was complete in all patients after 2 hours, and in 100%, 81% and 44% on days 14, 21, and 28 respectively. A pharmocodynamic correlation model showed minimal enzymatic activity of 0.2 IU/ml for optimal asparagine depletion. The kinetic POSTHOC analyses demonstrated enzymatic activity for 3 weeks or more. One patient developed neutralizing anti-asparaginase antibodies on day 22 post administration. Pegaspargase was well tolerated with few grade 3/4 side effects. No allergic reactions or pancreatitis were observed. In adults 55 years old or younger, pegaspargase produces a long duration of asparagine depletion, and can be given intravenously, with a safety profile that is similar to equivalent multiple doses of intramuscular E. coli asparaginase .
