PHARMACOKINETICS AND TOXICITY OF METHOTREXATE IN CHILDREN WITH DOWN-SYNDROME AND ACUTE LYMPHOCYTIC-LEUKEMIA
PHARMACOKINETICS AND TOXICITY OF METHOTREXATE IN CHILDREN WITH DOWN-SYNDROME AND ACUTE LYMPHOCYTIC-LEUKEMIA
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DOI：
10.1016/s0022-3476(87)80131-2
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发表时间：
1987-10-01
影响因子：
5.1
通讯作者：
EVANS, WE
中科院分区：
文献类型：
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作者：
GARRE, ML;RELLING, MV;EVANS, WE
患有唐氏综合症和急性淋巴细胞白血病（ALL）的儿童对甲氨蝶呤（MTX）等抗肿瘤药物的耐受性较差。我们评估了 5 名接受多次高剂量 MTX (1 g/m2) 的唐氏综合症和 ALL 患者的 MTX 药代动力学和毒性。根据性别、种族、年龄和初始白细胞计数，将三名无唐氏综合症的对照患者与每个病例进行匹配。输注后 42 小时测量的中位 MTX 血浆浓度明显高于对照患者（平均分别为 0.47 和 0.24 μmol/L，P = 0.03）。当使用 0.5 μmol/L 的 42 小时 MTX 浓度来识别有毒性风险的患者时，唐氏综合症患者（62 例中的 31 例，50%）比对照患者（214 例中的 13 例，6.1%，P < 0.0001）有更多疗程被认为具有高毒性风险。唐氏综合症患者的平均 MTX 清除率为 64.1 mL/min/m2，而平均对照值为 80.6 mL/min/m2 (P = 0.13)。每次高剂量 MTX 疗程后的毒性根据标准化标准进行分级。与对照患者（分别为 3.6% 和 0.9%，P < 0.0001）相比，唐氏综合症患者（分别为 36% 和 13.4%）发生 2 至 4 级胃肠道毒性以及 3 和 4 级血液毒性的频率更高。尽管向所有唐氏综合症患者给予较高剂量的亚叶酸并延长了持续时间，但这种较高频率的毒性还是发生了。我们得出的结论是，MTX 药代动力学的改变可能导致唐氏综合症患者中 MTX 诱导的毒性发生率更高。
Children with Down syndrome and acute lymphocytic leukemia (ALL) have poor tolerance to antineoplastic drugs, including methotrexate (MTX). We evaluated MTX pharmacokinetics and toxicity in five patients with Down syndrome and ALL who had received multiple hihg doses of MTX (1 g/m2). Three control patients without Down syndrome were matched to each case according to sex, race, age, and initial leukocyte count. Median MTX plasma concentrations, measured 42 hours after infusion, were significantly higher in patients with Down syndrome versus control patients (average 0.47 vs 0.24 .mu.mol/L, respectively, P = 0.03). When a 42-hour MTX concentration of 0.5 .mu.mol/L was used to identify patients at risk for toxicity, more courses were considered at high risk for toxicity among patients with Down syndrome (31 of 62, 50%) than in control patients (13 of 214, 6.1%, P < 0.0001). The average MTX clearance was 64.1 mL/min/m2 in Down syndrome vs an average control value of 80.6 mL/min/m2 (P = 0.13). Toxicity after each high-dose MTX course was graded according to standardized criteria. Grades 2 through 4 gastrointestinal toxicity and grades 3 and 4 hematologic toxicity occurred more frequently in the patients with Down syndrome (36% and 13.4% of courses, respectively) vs the control patients (3.6% and 0.9%, respectively, P < 0.0001 for both). This higher frequency of toxicity occurred despite higher doses and prolonged duration of leucovorin given to all patients with Down syndrome. We conclude that altered MTX pharmacokinetics may contribute to the higher incidence of MTX-induced toxicity seen in patients with Down syndrome.