大剂量MTX不同给药方式治疗淋巴瘤的药效学及药代动力学研究

A Study to Compare the Pharmacodynamics and Pharmacokinetics of two Regimens of High-dose Methotrexate in Patients with Lymphoma

目的分析接受HD-MTX不同给药方式(6h或24h持续静脉滴注)治疗患者的药代动力学特征及疗效,并探讨较佳的给药方式。方法对96例非霍奇金淋巴瘤患者采用HD-MTX(1～6.1g/m2)6h或24h持续静脉滴注(共364个疗程),采用高效液相色谱法,测定MTX停用后不同时间的血药浓度,比较HD-MTX2种给药方式的血药浓度、不良反应和疗效。结果6h给药组0h、24h中位血清MTX浓度分别为73.75μmol/L和0.36μmol/L,明显高于24h给药组(52.25μmol/L和0.09μmol/L)(P均<0.01)。6h给药组、24h给药组Ⅲ～Ⅳ度血液学毒性发生率分别为32.5%、45.4%(P=0.122),Ⅱ～Ⅳ度非血液学毒性发生率分别为12.5%、22.5%(P=0.145)。Ⅱ～Ⅲ度口腔黏膜炎均发生在24h给药组。6h给药组、24h给药组3年中枢复发率分别为0、1.5%。结论大剂量MTX静脉滴注6h给药血清MTX浓度较静脉滴注24h更高。2种给药方式均能有效地预防淋巴瘤或白血病中枢转移,但前者口腔黏膜毒性明显低于后者,是较佳的给药方式。

Objective A retrospective analysis to compare the treatment outcomes,pharmacokinetics of two regimens of HD-MTX（ 6-hour or 24-hour continuous venous infusion） so as to search for the more preferable administration of HD-MTX. Methods Ninety-six non-Hodgkin＇ s lymphoma patients were treated with either 6-hour or 24-hour continuous venous infusion of MTX （ 1 -6.1g/m^2 ,total 364 courses）. Serum MTX concentration at 0h,24h,48h,after the end of HD-MTX infusion was measured by high-pressure liquid chromatography. Compare the MTX serum concentration, toxicities and efficacy between the two groups. Results The median serum concentration of MTX at Oh and 24 h after the end of HD-MTX infusion was significant higher in 6-hour group than in 24-hour group（0h,73.75 μmol/L VS 52.25 μmol/L;24 h,0.36 μmol/L VS 0.09 μmol/L,both two P 〈0.01 ）. Grade Ⅲ -Ⅳ myelosuppresion rate in 6-hour group and 24-hour group is 32.5% ,45.4% （P =0. 122） ,respectively. Grade Ⅱ - Ⅳ non-hematologic toxieities between 6-hour group and 24-hour group is no significant difference （12.5% VS 22.5% ,P =0. 145）. Grade Ⅱ - Ⅲ mucositis all happened in 24 h group. The CNS relapse rate of three years for 6-hour group and 24-hour group was 0 and I. 5% , respectively. Conclusion Six-hour continuous venous infusion of HD-MTX can achive higher serum MTX concentration than with 24-hour infusion. Both the two regimens are effective to prevent CNS relapse. However,the mucositis observed in patients with 6-hour continuous venous infusion is lower than in patients with 24-hour infusion. HD-MTX administrated by 6-hour continuous venous infusion is more preferable than by 24-hour infusion.