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

Abstract

BackgroundChildren 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 MethodsWe compared methotrexate-induced toxicity and pharmacokinetics in a retrospective casecontrol 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. ResultsOverall, 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. ConclusionsWe 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 pharmacodynamic 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.Key words: metrotrexate pharmacokinetics, Down syndrome, acute lymphoblastic leukemia, methotrexate.Citation: Buitenkamp TD, Mathôt RAA, de Haas V, Pieters R, and Zwaan CM. Methotrexateinduced side effects are not due to differences in pharmacokinetics in children with Down's syndrome and acute lymphoblastic leukemia. Haematologica 2010;95:01106-1113. doi:10.3324/haematol.2009

Genome-wide study of methotrexate clearance replicates SLCO1B1

“…Of the 1883 patients treated with HDMTX on P9904 and P9905, 1588 were eligible and had germline DNA evaluable. 6 Patients who had congenital abnormalities (usually Down syndrome, which is known to affect methotrexate clearance) [13][14][15] or who did not have any courses that passed methotrexate quality control were excluded ( Figure 1). Demographic information on the patients included can be found in supplemental Table 1.…”

Acute leukemia in children with Down syndrome

“…The report by Buitenkamp et al in this issue of the Journal addresses whether differences in pharmacokinetics could account for differences in drug sensitivity and toxicity seen in children with Down syndrome and ALL. 33 Methotrexate pharmacokinetics were analyzed retrospectively in children with ALL, comparing 44 with Down syndrome and 87 without the syndrome. 33 Using non-linear mixed effect modeling, no differences in methotrexate pharmacokinetics were found between patients with and without Down syndrome which could explain the significantly higher proportion of children with Down syndrome who experienced methotrexate-induced gastrointestinal toxicity.…”

“…33 Methotrexate pharmacokinetics were analyzed retrospectively in children with ALL, comparing 44 with Down syndrome and 87 without the syndrome. 33 Using non-linear mixed effect modeling, no differences in methotrexate pharmacokinetics were found between patients with and without Down syndrome which could explain the significantly higher proportion of children with Down syndrome who experienced methotrexate-induced gastrointestinal toxicity. The authors concluded that the higher toxicities suffered by Down syndrome patients are probably related to pharmacodynamic differences of the gastrointestinal mucosa and that intermediate doses of methotrexate (such as 1-3 g/m 2 ) can be used safely in Down syndrome children with ALL.…”

Acute Leukemia in Down Syndrome Children, A Morroccan Retrospective Review

“…The authors concluded that the higher toxicities suffered by Down syndrome patients are probably related to pharmacodynamic differences and that intermediate doses of methotrexate (such as 1-3 g/ m 2 ) can be used safely in Down syndrome children with ALL [7].…”