[l-folinic acid versus racemic folinic acid in the treatment of leukemia in children with high dose of methotrexate].
Until now, folinic acid (FA) has been available the racemic mixture d1 FA, whose biological activity is supported by natural 1 FA. The purpose of this trial was to compare, on a pharmacokinetic, biological, and clinical basis, the racemic mixture dl FA with the pure 1 FA in the rescue of high-dose methotrexate (MTX) therapy. Eighteen children with acute lymphocytic leukemia (ALL) were entered in this trial planned with a cross-over design. Four cycles of MTX (5 g/m2, 24h CVI) were administered to each patient, with a 2-week interval between cycles. The rescue was achieved orally every 6h, starting 12h after the end of the MTX infusion, at a dose of 12 mg/m2 for dl FA and 6 mg/m2 for pure 1 FA. dl FA and 1 FA rescues were alternated from one cycle to the next. d FA, 1 FA, and the active metabolite 5-methyltetrahydrofolate (5-MTHF) were measured in plasma using a stereospecific HPLC assay. After administration of dl FA, the accumulation of d FA in plasma was confirmed: mean residual concentrations were 420 and 652 nM after 2 and 6 intakes respectively. Total active folate concentrations (1 FA + 5-MTHF) were similar between the two types of rescue: 92 and 100 nM respectively for dl FA rescue and 1 FA rescue after two intakes, 186 and 184 nM respectively for dl FA rescue and 1 FA rescue after six intakes. Intra-individual statistical analysis of total active folates (1 FA + 5-MTHF) performed on 17 patients did not show any significant difference between dl FA rescue and 1 FA rescue. For both types of rescue, MTX terminal half-lives were identical (average value 13.9 h). Considering each type of toxicity (hematologic, hepatic, renal and digestive) there was no significant difference in the proportion of toxic cycles following l FA rescue or dl FA rescue. In conclusion, the administration of the pure l FA, as compared with the administration of the racemic mixture, results in comparable blood profiles of active folates and MTX, and leads to equivalent treatment tolerance.
Etienne
M C
MC
Centre Antoine-Lacassagne, Nice, France.
Thyss
A
A
Bertrand
Y
Y
Rubie
H
H
Milano
G
G
D000293:Adolescent; D000931:Antidotes / Q000008:administration & dosage* / Q000493:pharmacokinetics; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007223:Infant; D002955:Leucovorin / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008727:Methotrexate / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood / Q000188:drug therapy*; D013237:Stereoisomerism
D000931:Antidotes; D002955:Leucovorin; D008727:Methotrexate
Acide folinique forme 1 pure versus acide folinique forme racémique dans le traitement de la leucémie de l'enfant par méthotrexate forte dose.