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 microM to < 2 microM 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 microM and fell to < 0.25 microM by 48 h in five of six animals. CSF L-asparagine concentrations remained below 0.25 microM 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.
Berg
S L
SL
Pediatric Branch, National Cancer Institute, Bethesda, Maryland 20892.
Balis
F M
FM
McCully
C L
CL
Godwin
K S
KS
Poplack
D G
DG
D000622:Aminolevulinic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001215:Asparaginase / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001216:Asparagine / Q000097:blood* / Q000134:cerebrospinal fluid*; D002851:Chromatography, High Pressure Liquid; D004800:Enzymes, Immobilized; D007273:Injections, Intramuscular; D007527:Isoenzymes; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000493:pharmacokinetics*
D000970:Antineoplastic Agents; D004800:Enzymes, Immobilized; D007527:Isoenzymes; C002199:5-diazo-4-oxonorvaline; D011092:Polyethylene Glycols; D001216:Asparagine; C042705:pegaspargase; D000622:Aminolevulinic Acid; D001215:Asparaginase