建立儿童患者群体药代动力学依从性模型的研究

Measuring adherence using lamivudine concentration monitoring in young children

目的本研究通过儿童患者的拉米夫定群体药代动力学研究,建立了拉米夫定群体药代动力学模型,探讨进行患者依从性评价的参考浓度。方法 68名感染HIV的儿童患者接受常规抗逆转录病毒治疗,每名患者采集4～8个拉米夫定的稳态血药浓度数据,用NONMEM 7软件建立群体药代动力学模型,探讨进行患者依从性评价的参考浓度。结果拉米夫定清除率随体重增加成指数增加,并随年龄的增加以Emax渐进性曲线模型达到成熟。10 kg儿童的成熟清除率为12.1 L·h-1,其成熟半衰期为4个月。本研究发现拉米夫定存在明显的昼夜节律,夜晚的清除率比白天低16.7%,因此在采集治疗药物监测样本时需要区分早、晚浓度。拉米夫定清除率的个体间变异非常小,可以用于预测患者依从性评价的参考药物浓度。结论本研究确立了评价儿童患者依从性的参考浓度,可用血药浓度监测结果与参考浓度相比较,简单、准确判断儿童患者的依从性。

Objective To establish a population pharmacokinetic model of lamivudine describing the variability of its concentrations in young children,and explore the reference lamivudine concentrations for adherence investigation.Methods The steady state pharmacokinetics of lamivudine were evaluated in 68 young children infected with HIV and receiving antiretroviral treatment twice daily with or without concomitant antitubercular treatment.A population pharmacokinetic analysis was conducted by using NONMEM 7 software.Results Allometric scaling of body mass index（BMI） was applied to oral clearance and volume of distribution.Clearance was found to mature with age in sigmoidal relationship：the clearance at full maturation is 12.1 L·h-1 in a 10 kg child,and it reaches half of this value in 4 months.Oral clearance of lamivudine was found to be 16.7% lower in overnight.The variability of clearance was small so that simulations could accurately predict lamivudine concentrations.Reference values for lamivudine concentrations that can be used to evaluate adherence to treatment were proposed.Conclusion The lamivudine concentration measurement could be used to assess treatment adherence.