Morphine Glucuronidation in Preterm Neonates, Infants and Children Younger than 3 Years
Morphine Glucuronidation in Preterm Neonates, Infants and Children Younger than 3 Years
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DOI：
10.2165/00003088-200948060-00003
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发表时间：
2009-01-01
影响因子：
4.5
通讯作者：
Tibboel, Dick
中科院分区：
文献类型：
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作者：
Knibbe, Catherijne A. J.;Krekels, Elke H. J.;Tibboel, Dick
背景和目的：相当数量的儿童药物使用仍然是未经许可或标签外的。为了得出合理的给药方案，以吗啡及其主要代谢物为模型药物，研究了衰老对新生儿（包括早产儿、婴儿和3岁以下儿童）糖醛酸化能力的影响。方法：采用非线性混合效应建模软件NONMEM (R) V建立群体药代动力学模型，以248例体重500 g ~ 18 kg（中位2.8 kg）静脉注射吗啡的婴儿的2159个吗啡及其葡萄糖醛酸盐浓度为基础。使用归一化预测分布误差对模型进行内部验证。结果：吗啡对葡萄糖醛酸酯的形成清除率和葡萄糖醛酸酯的消除清除率主要受体重的影响，其参数化使用异速生长方程，估计指数标度因子为1.44。此外，出生年龄小于10天被确定为葡萄糖醛酸酯形成清除的协变量，独立于出生体重或月经后年龄。分配体积与体重成线性比例。结论：基于模型的模拟显示，在新生儿（包括早产儿、婴儿和3岁以下儿童）中，以mu g/kg表示的负荷剂量和以mu g/kg(1.5)/h表示的维持剂量，在10天以下的新生儿中维持剂量减少50%，导致吗啡和代谢物在整个研究年龄范围内的血清浓度范围狭窄。未来的药效学研究需要揭示这一人群的目标浓度，之后可以提出最终的剂量建议。
Background and objective: A considerable amount of drug use in children is still unlicensed or off-label. In order to derive rational dosing schemes, the influence of aging on glucuronidation capacity in newborns, including preterms, infants and children under the age of 3 years was studied using morphine and its major metabolites as a model drug.Methods: A population pharmacokinetic model was developed with the nonlinear mixed-effects modelling software NONMEM (R) V, on the basis of 2159 concentrations of morphine and its glucuronides from 248 infants receiving intravenous morphine ranging in bodyweight from 500 g to 18 kg (median 2.8 kg). The model was internally validated using normalized prediction distribution errors.Results: Formation clearances of morphine to its glucuronides and elimination clearances of the glucuronides were found to be primarily influenced by bodyweight, which was parameterized using an allometric equation with an estimated exponential scaling factor of 1.44. Additionally, a postnatal age of less than 10 days was identified as a covariate for formation clearance to the glucuronides, independent of birthweight or postmenstrual age. Distribution volumes scaled linearly with bodyweight.Conclusions: Model-based simulations show that in newborns, including preterms, infants and children under the age of 3 years, a loading dose in mu g/kg and a maintenance dose expressed in mu g/kg(1.5)/h, with a 50% reduction of the maintenance dose in newborns younger than 10 days, results in a narrow range of morphine and metabolite serum concentrations throughout the studied age range. Future pharmacodynamic investigations are needed to reveal target concentrations in this population, after which final dosing recommendations can be made.