Franken Linda G, Masman Anniek D, de Winter Brenda C M, Koch Birgit C P, Baar Frans P M, Tibboel Dick, van Gelder Teun, Mathot Ron A A
Department of Hospital Pharmacy, Erasmus Medical Centre, wytemaweg 80-na 219, 3015, Rotterdam, The Netherlands.
Palliative Care Centre, Laurens Cadenza, Rotterdam, The Netherlands.
Clin Pharmacokinet. 2016 Jun;55(6):697-709. doi: 10.1007/s40262-015-0345-4.
Morphine dosing can be challenging in terminally ill adult patients due to the heterogeneous nature of the population and the difficulty of accurately assessing pain during sedation. To determine the pharmacokinetics of morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) in this population, and to find clinically relevant parameters for dose individualisation, we performed a population pharmacokinetic analysis.
Blood samples were randomly collected from 47 terminally ill patients in both the pre-terminal and terminal phases. Nonlinear mixed-effects modelling (NONMEM) was used to develop a population pharmacokinetic model and perform covariate analysis.
The data were accurately described by a two-compartment model for morphine with two one-compartment models for both its metabolites. Typical morphine clearance was 48 L/h and fell exponentially by more than 10 L/h in the last week before death. Decreased albumin levels and a decreased estimated glomerular filtration rate (eGFR) resulted in lower metabolite clearance. Between-subject variability in clearance was 52 % (morphine), 75 % (M3G) and 79 % (M6G), and changed to 53, 29 and 34 %, respectively, after inclusion of the covariates.
Our results show that morphine clearance decreased up to the time of death, falling by more than 10 L/h (26 %) in the last week before death, and that M3G and M6G accumulated due to decreased renal function. Further studies are warranted to determine whether dose adjustment of morphine is required in terminally ill patients.
由于成年终末期患者群体的异质性以及在镇静期间准确评估疼痛的困难，吗啡给药具有挑战性。为了确定该群体中吗啡、吗啡 - 3 - 葡萄糖醛酸苷（M3G）和吗啡 - 6 - 葡萄糖醛酸苷（M6G）的药代动力学，并找到剂量个体化的临床相关参数，我们进行了群体药代动力学分析。
在终末期前和终末期从47例成年终末期患者中随机采集血样。采用非线性混合效应模型（NONMEM）建立群体药代动力学模型并进行协变量分析。
吗啡的二室模型及其两种代谢物的两个一室模型准确描述了数据。典型的吗啡清除率为48 L/h，在死亡前最后一周呈指数下降超过10 L/h。白蛋白水平降低和估计肾小球滤过率（eGFR）降低导致代谢物清除率降低。清除率的个体间变异性分别为52%（吗啡）、75%（M3G）和79%（M6G），纳入协变量后分别变为53%、29%和34%。
我们的结果表明，直至死亡时吗啡清除率降低，在死亡前最后一周下降超过10 L/h（26%），并且由于肾功能下降M3G和M6G蓄积。有必要进一步研究以确定成年终末期患者是否需要调整吗啡剂量。
