High-dose methotrexate: on the relationship of methotrexate elimination time vs renal function and serum methotrexate levels in 1164 courses in 264 Swedish children with acute lymphoblastic leukaemia (ALL).
OBJECTIVE
The objectives of the present study were to determine the relationship between methotrexate (MTX) elimination time and various aspects of renal function and to evaluate the prognostic value of elevated serum MTX and creatinine for delayed MTX elimination.


METHODS
The majority of the 264 children were being treated for ALL. According to the NOPHO-92 protocol, 5 or 8 g MTX/m(2) was administered over 24 h. Serum creatinine was assessed daily. In 11 patients from one centre, renal function was studied in more detail using serum cystatin C, iohexol clearance, and urinary albumin, IgG and protein HC.


RESULTS
Increased serum creatinine correlated significantly with the elimination time of MTX, whereas no indications were found of tubular or barrier function damage. Of the 1164 courses, 44 had delayed elimination of MTX (>/=120 h). Serum MTX >150 microM at the end of infusion had a sensitivity of 0.27 and a specificity of 0.94 to predict delayed MTX elimination, and >/=50% increase in serum creatinine during the first treatment day (creatinine ratio) had a sensitivity of 0.32 and a specificity of 0.99. The corresponding risk ratios were 5 and 19 for MTX >150 micro M and creatinine ratio, respectively. In courses with a normal elimination time (<72 h), 99% of the courses had a rise in serum creatinine of less than 50%.


CONCLUSIONS
Elevation of serum creatinine by more than 50% is a better predictor of delayed elimination than the level of serum MTX at the end of MTX infusion, especially if information on previous creatinine measurements is used to reduce the impact of an occasionally low serum creatinine value before the start of the MTX infusion.
Department of Clinical Pharmacology, Lund University Hospital, 221 85 Lund, Sweden. tor.skarby@klinfarm.lu.se
T
T
Skärby
P
P
Jönsson
L
L
Hjorth
M
M
Behrentz
O
O
Björk
E
E
Forestier
M
M
Jarfelt
G
G
Lönnerholm
P
P
Höglund
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D003404:Creatinine / Q000097:blood*; D005260:Female; D006801:Humans; D007223:Infant; D007668:Kidney / Q000187:drug effects*; D007677:Kidney Function Tests; D008297:Male; D008657:Metabolic Clearance Rate; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D013997:Time Factors; D016482:Urinalysis
D003404:Creatinine; D008727:Methotrexate