INTRODUCTION: Pregnant women are often excluded from clinical trials, creating a critical gap in safety data for many U.S. Food and Drug Administration (FDA)-approved drugs. This study aimed to identify compounds with favorable safety and pharmacokinetic profiles for pregnancy, focusing on agents that may reduce inflammation and prevent preterm birth (PTB). METHODS: We screened 3,113 FDA-approved compounds (Selleckchem) using ADMET LAB 2.0 for pharmacokinetics and ProTox 3.0 for toxicity. Drugs were categorized by mechanism of action and filtered based on gastrointestinal absorption, organ toxicity, neurotoxicity, respiratory toxicity, cardiotoxicity, mutagenicity, and anti-inflammatory potential. The top 50 candidates were further tested in a 3D-printed fetal–maternal interface device developed and validated in our laboratory. An inflammatory model was created by treating cultures with lipopolysaccharide (LPS, 100 ng/mL), and drug efficacy was assessed by measuring IL-6 and IL-8 production. RESULTS: Of the 3,113 compounds, 1,320 showed high absorption; 50 met all safety and pharmacokinetic criteria, including 5-HT receptor agonists, adrenergic receptor agonists, anti-infectives, and COX inhibitors. The LPS treatment significantly increased IL-6 and IL-8 levels compared to controls. Screening in the 3D-printed fetal–maternal interface revealed a broad range of efficacy among the 50 drugs, with several markedly reducing cytokine production. The most effective compounds were prioritized for further testing in organ-on-chip systems and animal models. CONCLUSIONS/IMPLICATIONS: Combining computational drug screening with a physiologically relevant inflammatory model enables efficient identification of pregnancy-safe, anti-inflammatory candidates. This integrated approach accelerates preclinical evaluation for PTB prevention and supports translation to organ-on-chip and animal studies for eventual clinical application.
Traub et al. (Thu,) studied this question.