期刊
CLINICAL PHARMACOKINETICS
卷 48, 期 6, 页码 371-385出版社
ADIS INT LTD
DOI: 10.2165/00003088-200948060-00003
关键词
-
资金
- Sophia Foundation for Scientific Research
- Erasmus Medical Center
- Sophia's Children's Hospital, Rotterdam, the Netherlands
- Dutch Organisation for Scientific Research (NWO)
- NICHD [HD45993, HD48689]
- NCRR [RR19729]
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH &HUMAN DEVELOPMENT [R01HD048689, U10HD045993] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR RESEARCH RESOURCES [K24RR019729] Funding Source: NIH RePORTER
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据