Glucarpidase, leucovorin, and thymidine for high-dose methotrexate-induced renal dysfunction: clinical and pharmacologic factors affecting outcome.
OBJECTIVE
To assess the role of the recombinant bacterial enzyme, glucarpidase (carboxypeptidase-G(2)), leucovorin, and thymidine in the management and outcome of patients with high-dose methotrexate (HDMTX) -induced nephrotoxicity.


METHODS
Patients with HDMTX-induced nephrotoxicity received one to three doses of intravenous (IV) glucarpidase and leucovorin rescue. The initial cohort (n = 35) also received thymidine by continuous IV infusion. Subsequently, thymidine was restricted to patients with prolonged exposure (> 96 hours) to methotrexate (MTX) or with substantial MTX toxicity at study entry. Plasma MTX, leucovorin, and 5-methyltetrahydrofolate (5-mTHF) concentrations were measured pre- and postglucarpidase. Toxicities were monitored, and logistic regression analysis was used to assess the relationship of baseline characteristics to the development of severe toxicity and death.


RESULTS
Glucarpidase was administered at a median of 96 hours (receiving thymidine, n = 44) and 66 hours (not receiving thymidine, n = 56) after the start of the MTX infusion. Plasma MTX concentrations decreased within 15 minutes of glucarpidase by 98.7%. Plasma 5-mTHF concentrations also decreased more than 98% after administration of glucarpidase. Of 12 deaths, six were directly attributed to irreversible MTX toxicity. Presence of grade 4 toxicity before administration of glucarpidase, inadequate initial increase in leucovorin dosing, and administration of glucarpidase more than 96 hours after the start of the MTX infusion were associated with development of grade 4 and 5 toxicity.


CONCLUSIONS
Early intervention with the combination of leucovorin and glucarpidase is highly effective in patients who develop HDMTX-induced renal dysfunction. Severe toxicity and mortality occurred in patients in whom glucarpidase rescue was delayed and occurred despite thymidine administration.
Widemann
Brigitte C
BC
Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD 20892-1101, USA. widemanb@mail.nih.gov
Balis
Frank M
FM
Kim
AeRang
A
Boron
Matthew
M
Jayaprakash
Nalini
N
Shalabi
Aiman
A
O'Brien
Michelle
M
Eby
Michelle
M
Cole
Diane E
DE
Murphy
Robert F
RF
Fox
Elizabeth
E
Ivy
Percy
P
Adamson
Peter C
PC
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination / Q000009:adverse effects; D005260:Female; D006801:Humans; D007223:Infant; D007674:Kidney Diseases / Q000097:blood / Q000139:chemically induced*; D002955:Leucovorin / Q000008:administration & dosage* / Q000097:blood; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D008875:Middle Aged; D013936:Thymidine / Q000008:administration & dosage* / Q000097:blood; D011623:gamma-Glutamyl Hydrolase / Q000008:administration & dosage* / Q000097:blood
D011623:gamma-Glutamyl Hydrolase; D002955:Leucovorin; D013936:Thymidine; D008727:Methotrexate