Pharmacokinetics of HD‐MTX in infants, children, and adolescents with non‐B acute lymphoblastic leukemia

Abstract

A retrospective pharmacokinetic analysis was done of methotrexate serum levels after high-dose treatment (HD-MTX, four cycles at two-week intervals of 5 g/sq.1m. over 24 h i.v.) in children with non-B acute lymphoblastic leukemia (ALL) with the specific aim of seeking differences in patients of different ages, including infants under one year. A total of 122 children (seven infants aged 3 months-1 year, 26 children aged 1-3 years, 68 children aged 3-10 years and 21 adolescents aged 10-15 years) with normal liver and renal function, receiving consolidation therapy at the Pediatric Clinic of Monza between May 1988 and April 1992, were enrolled in this study. MTX was given as an intravenous infusion in 24 h and serum concentrations were measured up to at least 72 h after the start of infusion by an enzyme immunoassay (TDX Abbot, Dallas, TX) in order to modulate folinic acid rescue. Pharmacokinetic analysis of MTX levels according to a two-compartment open model indicated that, compared to all children up to 10 years old, in adolescents older than 10 years the drug reached higher concentrations in serum and was cleared at a lower rate. Steady-state levels and AUC were from 60% higher to more than double and the total clearance of the compound, expressed either per square meter surface area or per kg body weight, in each cycle was significantly lower in adolescents > 10 years of age, sometimes being only one-third of the clearance in infants (0.2 vs. 0.6 1/h/kg and 6.6 vs. 10.7 1/h/sq.m). The relationship between each age and systemic clearance was highly significant as measured by regression analysis. Methotrexate systemic clearance progressively decreased as a function of age. Subsequent treatments did not induce changes in MTX pharmacokinetics. These data suggest that the better tolerance of HD-MTX in children may have a pharmacokinetic basis. The faster elimination of MTX in infants, who usually show the worst prognosis, suggests that full doses could be safely used in order to maximize the antileukemic effect without a high risk of toxicity.

Infants with acute lymphoblastic leukemia: no evidence for high methotrexate resistance

“…Data on the elimination of MTX in infants are somewhat conflicting, and not available in infants under the age of 2-3 months; however it seems that high doses of MTX are adequately tolerated. 8 Our data indicating that 1 g/m 2 i.v. achieved substantially higher MTX-PGs in infants than LDMTX suggest that higher doses of MTX are warranted in infants.…”

“…Based on these data, Ph-negative CML was diagnosed. Detection of the major BCR-ABL mRNA of bone marrow cells from this patient by RT-PCR analysis was performed as previously described, 8 using a primer ABL1 (5′-GGC CCA TGG TAC CAG GAG TG-3′) as a reverse transcription primer, followed by the amplification of cDNA with a first primer pair ABL1 and BCR1 (5′-GCT TCT CCC TGA CAT CCG TG-3′) for 35 cycles and a second primer pair ABL2 (5′-GTT TCT CCA GAC TGT TGA CTG-3′) and BCR2 (5′-GGA GCT GCA GAT GCT GAC CAA C-3′) for 35 cycles, respectively. RT-PCR analysis detected a 446 bp major BCR-ABL transcript, corresponding to b3a2 fusion (Figure 1c).…”

Identification of Risk Factors in High-Dose Methotrexate-Induced Acute Kidney Injury in Childhood Acute Lymphoblastic Leukemia

“…Low plasma protein is usually accompanied with the increased free plasma MTX level, and thus may cause MTX toxicities. The pharmacokinetics of HDMTX in children of different ages studied by Donelli et al [17] indicates that MTX clearance is lower in children over 10 years than in younger children, and can explain why older children are more likely to develop AKI.…”

Immune tolerance induction to enzyme-replacement therapy by co-administration of short-term, low-dose methotrexate in a murine Pompe disease model

“…Even though infants treated for acute lymphoblastic leukaemia appeared to tolerate 5 mg/m 2 of MTX without experiencing toxicities [39], our work focused upon decreasing MTX exposure while maintaining efficacy. A regimen of 0·5 mg/kg 3¥/week represents a MTX dose (the human equivalent dose for a 5-kg 3-month-old infant would be 0·6 mg/week), which is lower than the 7·5-15 mg/week used for the treatment of juvenile and adult rheumatoid arthritis.…”