用群体药物动力学方法指导个体化大剂量甲氨蝶呤用药

Individualized high-dose methotrexate dosing in childhood acute lymphoblastic leukemia with PPK method

目的:探讨用群体药物动力学(PPK)方法结合贝叶斯法对急性淋巴细胞性白血病(ALL)患儿的大剂量甲氨蝶呤(HDMTX)的剂量个体化的效果。方法:荧光偏振免疫法(fluorescence polarization immunoassay,FPIA)测定MTX血浆浓度。根据已建立的HDMTX的PPK模型结合MTX开始后第1h和第6h的血浆浓度,用贝叶斯法对11个患者的45个疗程HD-MTX的剂量个体化。结果:3g/m2HDMTX组,预测Cpss在目标值范围内的22个疗程中有20个疗程的实测Cpss在目标范围内;分别有14个和2个疗程的预测Cpss值低于和高于目标范围,经贝叶斯法调整剂量后,仍有1个疗程的实测Cpss低于目标范围。5g/m2HDMTX组,Cpss预测值在目标值范围内的5个疗程,实测Cpss均在目标范围内;预测值高于目标范围的2个疗程经贝叶斯法减少剂量后,实测Cpss也均在Cpss目标范围内。MTX开始静滴后第6h的血药浓度与预测Cpss和MTX的全身清除率有较好的相关性,MTX开始静滴后第1h的血药浓度与第6h的血药浓度及预测Cpss无相关性。结论:通过对45个疗程HDMTX的个体化研究,发现HDMTX的PPK模型预测较准确,个体化效果较好。

Objective：To probe the effect of individualizing high-dose methotrexate （HDMTX） in childhood acute lymphoblastic leukemia with established population pharmacokinetic （PPK） model of HDMTX. Methods：Fluorescence polarization immunoassay （FPIA） was used to determine plasma MTX concentrations. The doses of HDMTX for 45 therapeutic courses of HDMTX were adjusted based on the PPK model of HDMTX established by us and on the plasma MTX concentrations of 1 hour and 6 hours after the start of MTX with Bayesian method. Results：The predicted values of MTX Cpss of 27 therapeutic courses were calculated, finally, the observed values of 25 courses were within the Cpss target rang. The predicted values of MTX Cpss of 18 therapeutic courses were not within the Cpss target range, finally, the observed values of 17 were within the Cpss target rang by adjusted doses. Totally, the observed values of MTX Cpss of 42 （93.3%） therapeutic courses were within the Cpss target range. Conclusion：The observed values of MTX Cpss were close to the predicted ones. The effect of individualized MTX dosing was satisfied.