COMPARATIVE PHARMACOKINETIC STUDIES OF 3 ASPARAGINASE PREPARATIONS

Purpose: As part of pharmacologic studies of asparaginase (ASNase), we determined the half-life of ASNase activity and protein, and the effect of dose, repeated doses, different drug preparations, and hypersensitivity reactions on the half-life (t( 1/2 )) of serum ASNase activity. Patients and Methods: We measured ASNase activity (spectrophotometric assay) in serum samples obtained from patients with acute lymphoblastic leukemia (ALL) at various times during their therapy with intramuscular ASNase. ASNase protein was measured by enzyme-linked immunoadsorbent assay (ELISA). Results: Studies following the initial dose of Escherichia coli-derived ASNase demonstrated no difference in apparent t( 1/2 ) following 25,000 IU/m2 versus 2,500 IU/m2 (1.24 v 1.35 days, P = .2). The apparent t( 1/2 )s following maintenance doses of E coli ASNase (middle dose t( 1/2 ), 1.28 days, or last dose t( 1/2 ), 1.14 days) showed no difference when compared with the initial dose of ASNase (P = .3 to .9). There was no significant difference between the apparent t( 1/2 )s of ASNase activity and ASNase protein (n = 8, P = .2 to .6). The serum t( 1/2 ) was 0.65 and 5.73 days for patients receiving Erwinia or polyethylene glycol (PEG)-modified E coli ASNase, respectively, as the induction dose. ASNase activity was undetectable in sera of four patients studied in the week following an anaphylactic reaction to E coli ASNase and the t( 1/2 ) was significantly shorter in five patients with a history of allergic reaction to E coli ASNase who were studied following a dose of PEG ASNase, (t( 1/2 ), 1.80 days). Conclusion: We conclude that (1) the apparent t( 1/2 ) of ASNase is dependent on enzyme preparation used, but is not affected by dose or by repeated use; (2) the apparent t( 1/2 ) of E coli ASNase as a protein is the same as the apparent t( 1/2 ) of enzymatic activity; and (3) patients who have had a hypersensitivity reaction to E coli ASNase have a decreased apparent t( 1/2 ) with both E coli and PEG ASNase.