PHARMACOKINETICS OF PEG-L-ASPARAGINASE AND PLASMA AND CEREBROSPINAL-FLUID L-ASPARAGINE CONCENTRATIONS IN THE RHESUS-MONKEY

The pharmacokinetics of the polyethylene glycol-conjugated form of the enzyme L-asparaginase and the depletion Of L-asparagine from the plasma and cerebrospinal fluid (CSF) following an i. m. dose of 2500 IU/m2 PEG-L-asparaginase was studied in rhesus monkeys. PEG-L-asparaginase activity in plasma was detectable by 1 h after injection and maintained a plateau of approximately 4 IU/ml for more than 5 days. Subsequent elimination from plasma was monoexponential with a half-life of 6 +/- 1 days. Plasma L-asparagine concentrations fell from pretreatment levels of 14-47 muM to <2 muM by 24 h after injection in all animals and remained undetectable for the duration of the 25-day observation period in four of six animals. In two animals, plasma L-asparagine became detectable when the PEG-L-asparaginase plasma concentration dropped below 0.1 IU/ml. Pretreatment CSF L-asparagine levels ranged from 4.7 to 13.6 muM and fell to <0.25 muM by 48 h in five of six animals. CSF L-asparagine concentrations remained below 0.25 muM for 10- 14 days in four animals. One animal had detectable CSF L-asparagine concentrations within 24 h and another had detectable concentrations within 1 week of drug administration despite a plasma PEG-L-asparaginase activity profile that did not differ from that of the other animals. These observations may be useful in the design of clinical trials with PEG-L-asparaginase in which correlations among PEG-L-asparaginase pharmacokinetics, depletion of L-asparagine, and clinical outcome should be sought.