Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands.
Int J Pharm. 2011 Aug 30;415(1-2):9-14. doi: 10.1016/j.ijpharm.2011.02.056. Epub 2011 Mar 3.
Despite profound differences in response between children and adults, and between children of different ages, drugs are still empirically dosed in mg/kg in children. Since maturation of expression and function is typically a non-linear dynamic process which differs between biotransformation routes and pharmacological targets, paediatric dosing regimens should be based on the changing pharmacokinetic-pharmacodynamic (PKPD) relationship in children. In this respect, the population approach is essential, allowing for sparse sampling in each individual child. An example is presented on morphine glucuronidation, for which two covariates were identified and subsequently used to derive a model-based dosing algorithm for a prospective clinical trial in children. Using this novel dosing algorithm, similar morphine concentrations are expected while, depending on age, lower and higher morphine dosages are administered compared to mg/kg/h dosing. As the covariate functions may reflect system-specific information on the maturation of a specific drug-disposition pathway, its use for other drugs that share the same pathway is explored. For this purpose, prospective clinical trials and cross-validation studies are urgently needed. In conclusion, PKPD modelling and simulation studies are important to develop evidence-based and individualized dosing schemes for children, with the ultimate goal to improve drug safety and efficacy in this population.
尽管儿童和成人之间以及不同年龄的儿童之间的反应存在显著差异，但药物仍以毫克/公斤的剂量在儿童中进行经验性给药。由于表达和功能的成熟通常是一个非线性动态过程，并且在生物转化途径和药理学靶标之间存在差异，因此儿科给药方案应基于儿童中不断变化的药代动力学-药效学（PKPD）关系。在这方面，群体方法是必不可少的，允许在每个个体儿童中进行稀疏采样。以吗啡葡萄糖醛酸化为例，确定了两个协变量，并随后用于为儿童前瞻性临床试验推导出基于模型的给药算法。使用这种新的给药算法，预计会有类似的吗啡浓度，而根据年龄的不同，与毫克/公斤/小时给药相比，吗啡的剂量会更低或更高。由于协变量函数可能反映了特定药物处置途径成熟的系统特异性信息，因此探索了其在具有相同途径的其他药物中的应用。为此，迫切需要前瞻性临床试验和交叉验证研究。总之，PKPD 建模和模拟研究对于为儿童制定基于证据和个体化的给药方案非常重要，最终目标是提高该人群的药物安全性和疗效。
