title: High-dose methotrexate: pharmacokinetics in children and young adults.
abstract: Pharmacokinetics of methotrexate (MTX) was studied in 34 patients (age 1-25 years, median 12 years) predominantly with primary brain tumors and osteosarcoma, who received a total of 64 high-dose infusions (12 g/m2/4 h, maximum dose 20 g), followed by leucovorin rescue (COSS 82). Serum samples were collected over a period of at least 72 h after the end of infusion and MTX was measured by enzyme immunoassay (EMIT). The data were fitted to a biexponential equation using a nonlinear regression analysis. The concentration-time decay of MTX in serum observed in 29/34 patients receiving 4 x 15 mg/m2/d p.o. leucovorin up to 5 days was biphasic with mean half-lives (+/- SD) of 2.42 +/- 0.45 h for t1/2 alpha and 19.9 +/- 7.6 h for t1/2 beta. The steady-state volume of distribution (Vss) was 0.56 +/- 0.18 l/kg and the total body clearance (CL) 71 +/- 20 ml/min/m2 (mean +/- SD). Peak serum concentrations ranged from 674-1778 mumol/l (mean +/- SD, 1201 +/- 293 mumol/l). In 5/34 patients who received a prolonged leucovorin rescue due to a delayed MTX elimination t1/2 alpha was greater than 3.1 h. The data of this study suggest that patients with MTX serum concentrations of less than or equal to 6.3 mumol/l at 24 h, less than or equal to 0.77 mumol/l at 48 h, and less than or equal to 0.33 mumol/l at 72 h after the end of infusion, and a t1/2 alpha of less than or equal to 3.1 h (97.5th percentiles) are at low risk of toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Institute of Clinical Chemistry, Hannover Medical Highschool, FRG.
authors.forename: E
authors.initials: E
authors.lastname: Raude
authors.forename: M
authors.initials: M
authors.lastname: Oellerich
authors.forename: P
authors.initials: P
authors.lastname: Weinel
authors.forename: M
authors.initials: M
authors.lastname: Freund
authors.forename: M
authors.initials: M
authors.lastname: Schrappe
authors.forename: H
authors.initials: H
authors.lastname: Riehm
authors.forename: H
authors.initials: H
authors.lastname: Poliwoda
mesh_terms: D000293:Adolescent; D000328:Adult; D000375:Aging / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D006207:Half-Life; D006801:Humans; D007223:Infant; D008727:Methotrexate / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D008727:Methotrexate