Prediction of Maternal and Fetoplacental Concentrations of Cefazolin, Cefuroxime, and Amoxicillin during Pregnancy Using Bottom-Up Physiologically Based Pharmacokinetic Models
Prediction of Maternal and Fetoplacental Concentrations of Cefazolin, Cefuroxime, and Amoxicillin during Pregnancy Using Bottom-Up Physiologically Based Pharmacokinetic Models
复制标题
DOI：
10.1124/dmd.121.000711
复制
发表时间：
2022-04-01
影响因子：
3.9
通讯作者：
Jamei, Masoud
中科院分区：
文献类型：
--
作者：
Abduljalil, Khaled;Ning, Jia;Jamei, Masoud
对母体和胎儿药物暴露的担忧突出了更好地了解药物通过胎盘屏障进入胎儿的必要性。本研究旨在使用基于生理学的药物动力学（PBPK）模型预测母体和胎儿的药物处置。Simcyp Simulator V20中详细的母体-胎盘-胎仔PBPK模型用于预测妊娠期间和分娩时头孢唑林、头孢呋辛和阿莫西林的母体和胎仔-胎盘暴露量。机械动力学模型包括母体、胎儿和胎盘参数在妊娠过程中的生理变化。胎盘动力学参数化使用渗透性参数确定这些化合物的理化性质。然后，将PBPK预测值与观察数据进行比较。完全自下而上的胎儿胎盘PBPK模型开发头孢呋辛，头孢唑林，阿莫西林没有任何参数拟合。非妊娠受试者和妊娠受试者的预测值均在观察值的2倍范围内。预测值与9项头孢呋辛母体（5项胎儿胎盘）研究、10项头孢唑林母体（5项胎儿胎盘）研究和6项阿莫西林母体（2项胎儿胎盘）研究中报告的观察到的药代动力学数据相匹配。PBPK模型中胎儿和母体系统参数的整合，以及用于计算胎盘渗透性的化合物相关参数，促进并扩展了母体-胎盘-胎儿PBPK模型的应用。所开发的模型也可用于设计临床试验和前瞻性地用于母体给药药物或意外暴露于环境毒物后的母胎风险评估。意义声明本研究探讨了整合的母体-胎盘-胎儿PBPK模型预测母体和胎儿组织暴露于通过被动扩散机制穿过胎盘的经肾脏消除的抗生素的性能。从药物的理化性质预测经胎盘渗透清除率。结果表明，PBPK方法可以同时预测任何胎龄的母体和胎儿的药物暴露，以支持其在母体-胎儿暴露评估中的应用。从dmd.aspetjournals.org下载，
Concerns over maternal and fetal drug exposures highlight the need for a better understanding of drug distribution into the fetus through the placental barrier. This study aimed to predict maternal and fetal drug disposition using physiologically based pharmaco-kinetic (PBPK) modeling. The detailed maternal-placental-fetal PBPK model within the Simcyp Simulator V20 was used to predict the maternal and fetoplacental exposure of cefazolin, cefuroxime, and amoxicillin during pregnancy and at delivery. The mechanistic dynamic model includes physiologic changes of the maternal, fetal, and placental parameters over the course of pregnancy. Placental kinetics were parametrized using permeability parameters deter-mined from the physicochemical properties of these compounds. Then, the PBPK predictions were compared with the observed data. Fully bottom-up fetoplacental PBPK models were developed for cefuroxime, cefazolin, and amoxicillin without any parameter fitting. Predictions in nonpregnant subjects and in pregnant subjects fall within 2-fold of the observed values. Predictions matched observed pharmacokinetic data reported in nine maternal (five fetoplacental) studies for cefuroxime, 10 maternal (five fetoplacental) studies for cefazolin, and six maternal (two fetoplacental) studies for amoxicillin. Integration of the fetal and maternal system parameters within PBPK models, together with compound-related parameters used to calcu-late placental permeability, facilitates and extends the applications of the maternal-placental-fetal PBPK model. The developed model can also be used for designing clinical trials and prospectively used for maternal-fetal risk assessment after maternally administered drugs or unintended exposure to environmental toxicants. SIGNIFICANCE STATEMENT This study investigates the performance of an integrated maternal-placental-fetal PBPK model to predict maternal and fetal tissue exposure of renally eliminated antibiotics that cross the placenta through a passive diffusion mechanism. The transplacental perme-ability clearance was predicted from the drug physicochemical properties. Results demonstrate that the PBPK approach can facili-tate the prediction of maternal and fetal drug exposure simulta-neously at any gestational age to support its use in the maternal-fetal exposure assessments. Downloaded from dmd.aspetjournals.org at