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目的研究呼吸暂停新生儿中茶碱的代谢规律,阐明不同胎龄、日龄等固定效应对茶碱药动学参数的影响。方法收集2006年1月—2008年12月收治的209例呼吸暂停新生儿的病历资料和茶碱血药浓度等常规监测资料,利用NONMEM程序建立茶碱的群体药动学模型并提取参数,通过Beyesian反馈法获得个体药动学参数并对药动学模型进行验证,结合临床效应确定血药浓度有效治疗范围。结果新生儿的清除能力较低,t1/2在30 h以上,围新生儿期更加明显。胎龄,日龄,体重和肝、肾功能等对茶碱清除率有显著影响。早产儿与足月儿的围新生儿期、晚新生儿期患儿茶碱群体药动学参数Ke分别为(0.018±s 0.005)、(0.021±0.007)h-1和(0.019±0.009)、(0.022±0.010)h-1,t1/2分别为(39±8)、(33±7)h和(36±9)、(32±8)h,CL分别为(11.4±2.0)、(19±5)mL.h-1.kg-1和(16±4)、(19±3)mL.h-1.kg-1,围新生儿与晚新生儿间均有显著差异(P<0.05)。按此设计治疗方案进行验证,改善呼吸暂停的疗效优于传统治疗(P<0.05)。茶碱有效治疗血药浓度范围为5～12 mg.L-1,以不超过15 mg.L-1较合适。结论茶碱在新生儿体内代谢个体差异大,尤其在围新生儿期,临床用药时须充分考虑胎龄,日龄,体重和肝、肾功能的影响。
Objective To study the metabolism of theophylline in apnea neonates and to elucidate the effects of fixed effects such as gestational age and age on the pharmacokinetic parameters of theophylline. Methods A total of 209 cases of apnea neonates were collected from January 2006 to December 2008 and their theophylline plasma concentration and other routine monitoring data were collected. The pharmacokinetic model of theophylline was established by NONMEM program and the parameters were extracted. Beyesian feedback method to obtain individual pharmacokinetic parameters and pharmacokinetic model validation, combined with clinical effects to determine the effective treatment of blood concentration range. Results Neonatal ability to clear low, t1 / 2 in more than 30 h, the perinatal period more obvious. Gestational age, age, body weight and liver and kidney function have a significant effect on the theophylline clearance rate. The pharmacokinetic parameters Ke of theophylline group were (0.018 ± s 0.005), (0.021 ± 0.007) h-1 and (0.019 ± 0.009), respectively, in perinatal neonates and full-term infants. (0.022 ± 0.010) h-1 and t1 / 2 were (39 ± 8), (33 ± 7) h and (36 ± 9), (32 ± 8) 19 ± 5) mL.h-1.kg-1 and (16 ± 4) and (19 ± 3) mL.h-1.kg-1 respectively. There was a significant difference between perinatal neonates and late neonates (P < 0.05). According to the design of treatment programs for validation, to improve the efficacy of apnea is better than the traditional treatment (P <0.05). Theophylline effective therapeutic blood concentration range of 5 ~ 12 mg.L-1, with no more than 15 mg.L-1 is more appropriate. Conclusion Theophylline metabolites in newborns vary significantly, especially in the perinatal period, the clinical medication must give full consideration to gestational age, age, body weight and liver and kidney function.