Pharmacokinetics of high-dose methotrexate in infants treated for acute lymphoblastic leukemia.
BACKGROUND
Interfant-99 was an international collaborative treatment protocol for infants with acute lymphoblastic leukemia (ALL).


METHODS
We collected data on 103 infants at the time of their first treatment with high-dose methotrexate (HD MTX), 5 g/m(2). Children <6 months of age received two-third of the calculated dose based on body surface area (BSA), children 6-12 months three-fourth of the calculated dose, and children >12 months full dose.


RESULTS
The median steady-state MTX concentration at the end of the 24-hr infusion was 57.8 microM (range 9.5-313). The median systemic clearance was 6.22 L/hr/m(2) BSA, and tended to increase with age (P = 0.099). Boys had higher clearance than girls, 6.77 and 5.28 L/hr/m(2) (P = 0.030), and tended to have lower median MTX concentration at 24 hr. Eight infants had MTX levels below 20 microM, a level judged to be sufficient in B-lineage ALL in children >1 year of age. All infants tolerated the dose well enough to receive a second dose of HD MTX without dose reduction. We found no significant effect on disease-free survival for MTX steady-state concentration, MTX clearance, or time to MTX below 0.2 microM.


CONCLUSIONS
Our data provide no support for a change in the dosing rules for MTX used in Interfant-99. However, in view of the poor treatment results for infants, one might consider increase in the dose for patients who reach plasma levels below median after the first MTX dose.
Lönnerholm
Gudmar
G
Department of Women's and Children's Health, University Hospital, Uppsala, Sweden. gudmar.lonnerholm@kbh.uu.se
Valsecchi
Maria Grazia
MG
De Lorenzo
Paola
P
Schrappe
Martin
M
Hovi
Liisa
L
Campbell
Myriam
M
Mann
Georg
G
Janka-Schaub
Gritta
G
Li
Chi-Kong
CK
Stary
Jan
J
Hann
Ian
I
Pieters
Rob
R
D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008727:Methotrexate / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D008727:Methotrexate