大剂量甲氨蝶呤目标浓度个体化调整研究

目的 探讨大剂量甲氨蝶呤(MTX)24 h输注治疗儿童急性淋巴细胞白血病目标浓度个体化调整的方法.方法 本研究涉及24例患儿105个疗程,检测MTX开始输注后第1和第6小时的血药浓度,根据已建立的大剂量MTX群体药物动力学模型,推算出该疗程稳态血药浓度(CSS)的预测值.根据CSS预测值,于MTX开始输注后第8小时调整MTX输注速度和剂量.MTX输注后第23小时再检测血药浓度(CSS实测值).结果 为达目标浓度,17例(71%)患儿进行了剂量调整.45个疗程(43%)调整了剂量,42个疗程增加了剂量,3个疗程减少了剂量.早期阶段(诱导缓解和巩固治疗方案后的大剂量MTX的疗程)29个疗程中有16个疗程增加了剂量,1个疗程减少了剂量;维持阶段76个疗程中有26个疗程增加了剂量,2个疗程减少了剂量.最终有95个(90%)疗程的CSS实测值达目标范围,8个疗程小于目标范围,2个疗程大于目标范围.如果不调整剂量,仅有74个(70%)疗程的CSS(不调整)在目标范围.调整MTX剂量,与不调整相比,可以明显增加CSS实测值达目标范围的疗程数(χ2=13.366,P=0.000).在剂量不调整的60个疗程中,CSS实测值和CSS预测值有较好的直线相关性(r=0.487,P=0.000);CSS实测值与MTX输注后第6小时的血药浓度也有一定的直线相关性(r=0.389,P=0.002).105个疗程MTX的总清除率(CL)实测值是(7.01±2.06)L/(m2·h).在所有疗程间CL相差最大达4.4倍,同一患儿不同疗程间CL相差最大达2.9倍.CL与患儿的年龄、体重和总胆红素呈直线负相关,与血磷呈直线正相关;化疗早期阶段疗程的CL有高于维持阶段疗程的倾向(P均＜0.05).结论 105个疗程大剂量MTX化疗,疗程间CL差异最大达4.4倍,需要目标浓度个体化调整.通过检测MTX输注后第1和第6小时的血药浓度,调整MTX输注速度和剂量,最终90%疗程的CSS实测值达目标范围.早期阶段大剂量MTX化疗更需要目标浓度个体化调整.

Investigation on individualized adjustment of target range of high-dose methotrexate

Objective To explore the way of individualized adjustment of target range of each high-dose methotrexate (MTX) 24 hours infusion to treat acute lymphoblastic leukemia in children.Methods Twenty-four children and 105 infusions were included in the study.According to 1 h and 6 h plasma MTX concentrations after infusion,based on established high-dose MTX population pharmacokinetics model,the course predicted value of drug concentration at steady state (CSS) was calculated.MTX infusion rate and dosage was adjusted 8 h after the start according to the predicted value of CSS.Then MTX concentration at 23 h (actual value of CSS) was measured.Results To achieve the target range of CSS,adjustments of MTX dosage were required in 17 (71%) patients.Adjustments of MTX dosage were required in 45 (43%) infusions,the dose was increased in 42 infusions and decreased in 3 infusions.There were 29 infusions of high-dose MTX during consolidation therapy (after remission induction therapy).Among them,16 infusions had increased dosage,and 1 infusion had decreased dosage.There were 76 infusions during maintenance therapy.Among them,26 infusions increased dosage,and 2 infusions decreased dosage.Overall 95 (90%) infusions achieved the target range of CSS,while in 8 infusions the doses were lower than the target range in 2 infusions the doses were higher than the target range.If there had been no adjustments,only 74 (70%) infusions could have achieved the target range.Adjustments of MTX dosage,compared with no adjustments,could remarkably enhance the rate of achieving the target range of CSS (χ2=13.366,P=0.000).Among 60 infusions of no adjustments,the actual values of CSS were well correlated with the predicted values of CSS (r=0.487,P=0.000),and the actual values of CSS were also correlated with the 6 h plasma MTX concentrations after infusions(r=0.389,P=0.002).The actual values of total clearance(CL)of MTX patient variability in CL was up to 2.9-fold.Predisposing factors that correlated with decreased CL of MTX were old age,heavy body weight,low blood phosphate,high blood bilirubin and infusions during maintenance therapy (P＜0.05). Conclusions High-dose methotrexate chemotherapy needed individualized adjustment,as inter-courses variability of CL was up to 4.4-fold among 105 infusions.According to 1 h and 6 h plasma MTX concentrations after infusion,adjusting MTX infusion rate and dosage,overall 90% infusions achieved the target range of CSS.High-dose MTX infusions during consolidation therapy needed individualized adjustment of target range more.