Pharmacokinetics of PEG-l-asparaginase and plasma and cerebrospinal fluidl-asparagine concentrations in the rhesus monkey

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Abstract
The pharmacokinetics of the polyethylene glycol-conjugated form of the enzymel-asparaginase and the depletion ofl-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. Plasmal-asparagine concentrations fell from pretreatment levels of 14–47 μM to M 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, plasmal-asparagine became detectable when the PEG-l-asparaginase plasma concentration dropped below 0.1 IU/ml. Pretreatment CSFl-asparagine levels ranged from 4.7 to 13.6 μM and fell to M by 48 h in five of six animals. CSFl-asparagine concentrations remained below 0.25 μM for 10–14 days in four animals. One animal had detectable CSFl-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 ofl-asparagine, and clinical outcome should be sought.