Pharmacokinetic study of methotrexate, folinic acid and their serum metabolites in children treated with high-dose methotrexate and leucovorin rescue.
The pharmacokinetics of methotrexate (MTX), 7-hydroxymethotrexate (7-OHMTX), 2,4-diaminomethylpteroic acid (APA), folinic acid, and 5-methyltetrahydrofolate (5-MTHF) have been studied during 21 high-dose MTX (HDMTX) infusions (5 g.m-2 in 24 h) with leucovorin (LCV) rescue, a component of the therapy of 5 children with acute lymphoblastic leukemia (ALL). The median steady-state concentration of MTX was 66 mumol.l-1. Three elimination half-lifes were determined for MTX: 1.8 h, 6.4 h and a terminal 15 h. The median systemic MTX clearance was 110 mg.m-2.min-1. The 7-OHMTX level increased during each infusion and a Cmax of 19 mumol.l-1 was achieved at the end. Its initial half-life was 5 h and the terminal half-life was 12 h. Thus, the peak serum concentration ratio of 7-OHMTX to MTX was reached 24 h after the end of the infusion at a median ratio of 8. The MTX metabolite APA was detected in concentrations less than 0.06 mumol.l-1. The median folinic acid level during rescue, 48 h after starting the infusion, was 7.0 mumol.l-1 and 18 h following the last dose of LCV it was 0.44 mumol.l-1, leading to ratios of folinic acid to MTX of 31 and 6, respectively. The median 5-MTHF level during rescue was 0.44 mumol.l-1 with a median ratio of 5-MTHF to MTX of 2. Twenty infusions with 48 h MTX levels of less than 0.5 mumol.l-1 were without marked toxicity. Only one patient with a 48 h MTX concentration of 5.5 mumol.l-1 and a ratio of 5-MTHF to MTX of 0.08 suffered from ulcerating mucositis and septicaemia despite increased and prolonged LCV rescue.
Wolfrom
C
C
Department of Pediatrics, Freie Universität Berlin, FRG.
Hepp
R
R
Hartmann
R
R
Breithaupt
H
H
Henze
G
G
D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D006207:Half-Life; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D008657:Metabolic Clearance Rate; D008727:Methotrexate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*
C000203:deoxyaminopteroic acid; D002955:Leucovorin; C011864:7-hydroxymethotrexate; D008727:Methotrexate