Pharmaceutical Sciences Research Center, Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing 210008, China; School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
Neonatal Intensive Care Unit, Children's Hospital of Nanjing Medical University, Nanjing 210008, China.
Pharmacol Res. 2022 Oct;184:106416. doi: 10.1016/j.phrs.2022.106416. Epub 2022 Aug 24.
Current standard-dose caffeine therapy results in significant intersubject variability. The aims of this study were to develop and evaluate population pharmacokinetic (PPK) models of caffeine in preterm infants through comprehensive screening of covariates and then to propose model-informed precision dosing of caffeine for this population. A total of 129 caffeine concentrations from 96 premature neonates were incorporated into this study. Comprehensive medical record and genotype data of these neonates were collected for analysis. PPK modeling was performed by a nonlinear mixed effects modeling program (NONMEM). Final models based on the current weight (CW) or body surface area (BSA) were evaluated via multiple graphic and statistical methods. The model-informed dosing regimen was performed through Monte Carlo simulations. In addition to CW or BSA, postnatal age, coadministration with erythromycin (ERY), and aryl hydrocarbon receptor coding gene (AHR) variant (rs2158041) were incorporated into the final PPK models. Multiple evaluation results showed satisfactory prediction performance and stability of the CW- and BSA-based models. Monte Carlo simulations demonstrated that trough concentrations of caffeine in preterm infants would be affected by concomitant ERY therapy and rs2158041 under varying dose regimens. For the first time, ERY and rs2158041 were found to be associated with the clearance of caffeine in premature infants. Similar predictive performance and stability were obtained for both CW- and BSA-based PPK models. These findings provide novel insights into caffeine precision therapy for preterm infants.
目前，标准剂量的咖啡因治疗会导致显著的个体间变异性。本研究的目的是通过全面筛选协变量，建立和评估早产儿咖啡因的群体药代动力学（PPK）模型，然后为该人群提出基于模型的咖啡因精准给药方案。本研究共纳入了 96 名早产儿的 129 个咖啡因浓度数据。收集了这些新生儿的综合病历和基因型数据进行分析。采用非线性混合效应建模程序（NONMEM）进行 PPK 建模。通过多种图形和统计方法评估基于当前体重（CW）或体表面积（BSA）的最终模型。通过蒙特卡罗模拟进行基于模型的给药方案。除 CW 或 BSA 外，还将出生后年龄、与红霉素（ERY）共同给药以及芳香烃受体编码基因（AHR）变异（rs2158041）纳入最终的 PPK 模型。多项评估结果表明，基于 CW 和 BSA 的模型具有良好的预测性能和稳定性。蒙特卡罗模拟表明，在不同剂量方案下，早产儿的咖啡因谷浓度会受到 ERY 治疗和 rs2158041 的影响。首次发现 ERY 和 rs2158041 与早产儿咖啡因清除率有关。基于 CW 和 BSA 的 PPK 模型均具有相似的预测性能和稳定性。这些发现为早产儿的咖啡因精准治疗提供了新的思路。
