Methotrexate-induced side effects are not due to differences in pharmacokinetics in children with Down syndrome and acute lymphoblastic leukemia

Abstract

Background: Children with Down syndrome have an increased risk of developing acute lymphoblastic leukemia and a poor tolerance of methotrexate. This latter problem is assumed to be caused by a higher cellular sensitivity of tissues in children with Down syndrome. However, whether differences in pharmacokinetics play a role is unknown.

Design and methods: We compared methotrexate-induced toxicity and pharmacokinetics in a retrospective case-control study between patients with acute lymphoblastic leukemia who did or did not have Down syndrome. Population pharmacokinetic models were fitted to data from all individuals simultaneously, using non-linear mixed effect modeling.

Results: Overall, 468 courses of methotrexate (1-5 g/m(2)) were given to 44 acute lymphoblastic leukemia patients with Down syndrome and to 87 acute lymphoblastic leukemia patients without Down syndrome. Grade 3-4 gastrointestinal toxicity was significantly more frequent in the children with Down syndrome than in those without (25.5% versus 3.9%; P=0.001). The occurrence of grade 3-4 gastrointestinal toxicity was not related to plasma methotrexate area under the curve. Methotrexate clearance was 5% lower in the acute lymphoblastic leukemia patients with Down syndrome (P=0.001); however, this small difference is probably clinically not relevant, because no significant differences in methotrexate plasma levels were detected at 24 and 48 hours.

Conclusions: We did not find evidence of differences in the pharmacokinetics of methotrexate between patients with and without Down syndrome which could explain the higher frequency of gastrointestinal toxicity and the greater need for methotrexate dose reductions in patients with Down syndrome. Hence, these problems are most likely explained by differential pharmaco-dynamic effects in the tissues between children with and without Down syndrome. Although the number of patients was limited to draw conclusions, we feel that it may be safe in children with Down syndrome to start with intermediate dosages of methotrexate (1-3 g/m(2)) and monitor the patients carefully.

Figure 1.

Methotrexate plasma levels and diagnostic plots of the population pharmacokinetic model. Methotrexate plasma levels at various time-points following the start of a 24 h methotrexate-infusion in DS-ALL: (A) n=152 courses in 44 patients and non-DS-ALL (B) n=316 courses in 87 patients. Each dot represents a plasma level in a patient measured at a given time-point. Plasma concentrations at 48 h were available for all patients whereas levels at 1 h and 24 h were only determined in some of the hospitals. In case of methotrexate levels of 48 h > 0.4 μmol/L, monitoring of methotrexate levels was continued. (C) The predicted methotrexate concentrations calculated by the NONMEM two-compartment model versus observed concentrations for all patients. The points are evenly distributed around the line of unity indicating the goodness of fit of the model. Deviations from the line are caused by intra- and inter-patient variability and residual variability. (D) Individually (Bayesian) predicted methotrexate concentrations versus observed concentrations for all patients. All dots are close to the line of unity indicating limited residual variability.

Figure 2.

Correlation of methotrexate area under the curve (AUC) versus gastrointestinal toxicity in the first methotrexate course in DS-ALL patients only. CTC: Common Toxicity Criteria for Adverse Events. CTC grade 0–2 and grade 3–4 versus the methotrexate AUC. Number of patients per subgroup: <1000 μmol/L*h: n=29, 1000–2000 μmmol/L*h: n=11, 2000–3000 μmmol/L*h: n=4.