Kammala Ananth K, Richardson Lauren S, Radnaa Enkhtuya, Han Arum, Menon Ramkumar
Division of Basic Science and Translational Research, Department of Obstetrics and Gynecology, The University of Texas Medical Branch at Galveston, Galveston, TX, United States.
Department of Electrical and Computer Engineering, Texas A&M University, College Station, TX, United States.
Front Pharmacol. 2023 Aug 17;14:1241815. doi: 10.3389/fphar.2023.1241815. eCollection 2023.
Preterm birth rates and maternal and neonatal mortality remain concerning global health issues, necessitating improved strategies for testing therapeutic compounds during pregnancy. Current 2D or 3D cell models and animal models often fail to provide data that can effectively translate into clinical trials, leading to pregnant women being excluded from drug development considerations and clinical studies. To address this limitation, we explored the utility of in silico simulation modeling and microfluidic-based organ-on-a-chip platforms to assess potential interventional agents. We developed a multi-organ feto-maternal interface on-chip (FMi-PLA-OOC) utilizing microfluidic channels to maintain intercellular interactions among seven different cell types (fetal membrane-decidua-placenta). This platform enabled the investigation of drug pharmacokinetics in vitro. Pravastatin, a model drug known for its efficacy in reducing oxidative stress and inflammation during pregnancy and currently in clinical trials, was used to test its transfer rate across both feto-maternal interfaces. The data obtained from FMi-PLA-OOC were compared with existing data from in vivo animal models and ex vivo placenta perfusion models. Additionally, we employed mechanistically based simulation software (Gastroplus®) to predict pravastatin pharmacokinetics in pregnant subjects based on validated nonpregnant drug data. Pravastatin transfer across the FMi-PLA-OOC and predicted pharmacokinetics in the in silico models were found to be similar, approximately 18%. In contrast, animal models showed supraphysiologic drug accumulation in the amniotic fluid, reaching approximately 33%. The results from this study suggest that the FMi-PLA-OOC and in silico models can serve as alternative methods for studying drug pharmacokinetics during pregnancy, providing valuable insights into drug transport and metabolism across the placenta and fetal membranes. These advanced platforms offer promising opportunities for safe, reliable, and faster testing of therapeutic compounds, potentially reducing the number of pregnant women referred to as "therapeutic orphans" due to the lack of consideration in drug development and clinical trials. By bridging the gap between preclinical studies and clinical trials, these approaches hold great promise in improving maternal and neonatal health outcomes.
早产率以及孕产妇和新生儿死亡率仍然是令人担忧的全球健康问题,因此需要改进在孕期测试治疗性化合物的策略。当前的二维或三维细胞模型以及动物模型常常无法提供能够有效转化为临床试验的数据,导致孕妇被排除在药物研发考量和临床研究之外。为了解决这一局限性,我们探索了计算机模拟建模和基于微流控的芯片上器官平台在评估潜在干预药物方面的效用。我们利用微流控通道开发了一种芯片上多器官胎儿-母体界面(FMi-PLA-OOC),以维持七种不同细胞类型(胎膜-蜕膜-胎盘)之间的细胞间相互作用。该平台能够在体外研究药物的药代动力学。普伐他汀是一种在孕期降低氧化应激和炎症方面具有疗效且目前正在进行临床试验的典型药物,被用于测试其在胎儿-母体两个界面的转运速率。将从FMi-PLA-OOC获得的数据与来自体内动物模型和体外胎盘灌注模型的现有数据进行了比较。此外,我们使用基于机制的模拟软件(Gastroplus®),根据经过验证的非孕期药物数据预测孕妇体内的普伐他汀药代动力学。发现普伐他汀在FMi-PLA-OOC上的转运以及在计算机模型中的预测药代动力学相似,约为18%。相比之下,动物模型显示羊水中药物超生理蓄积,达到约33%。本研究结果表明,FMi-PLA-OOC和计算机模型可作为研究孕期药物药代动力学的替代方法,为药物跨胎盘和胎膜的转运及代谢提供有价值的见解。这些先进平台为治疗性化合物的安全、可靠和快速测试提供了有前景的机会,有可能减少因在药物研发和临床试验中缺乏考量而被称为“治疗孤儿”的孕妇数量。通过弥合临床前研究和临床试验之间的差距,这些方法在改善孕产妇和新生儿健康结局方面具有巨大潜力。