Drug Repurposing in Pre‐Eclampsia: Maternal Pharmacokinetic and Pharmacodynamic Considerations for Clinical Trial Design

Pre-eclampsia is a hypertensive disorder of pregnancy affecting 3-8% of pregnancies worldwide, with no disease-modifying therapy currently available. Drug repurposing offers a promising strategy, yet no candidate has been validated to date. Pregnancy-associated physiological changes alter drug pharmacokinetics (PK), and pre-eclampsia itself may further modify drug disposition, complicating dose selection and contributing to inconclusive clinical trial outcomes. A structured literature search identified six prospective or randomized controlled trials of repurposed drugs for established pre-eclampsia: esomeprazole, omeprazole, sulfasalazine, pravastatin, recombinant antithrombin, and metformin. All drugs were well tolerated, with metformin the one to show promising clinical benefit by prolonging gestation; the remaining five drugs yielded inconclusive or null efficacy outcomes. Critically, PK sampling was conducted in only three trials, and none systematically characterized exposure-response relationships using key pre-eclampsia biomarkers, including soluble fms-like tyrosine kinase-1, soluble endoglin, and placental growth factor. Further common methodological limitations included small sample sizes (12-120 participants), heterogeneous gestational age eligibility criteria, and dosing regimens extrapolated from non-pregnant populations without pregnancy-specific optimization. These shortcomings likely contributed to the translational gap between promising preclinical findings and positive clinical trial outcomes. Model-informed drug development (MIDD) approaches, including physiologically based pharmacokinetic (PBPK) and population pharmacokinetic (popPK) modeling, optimal sampling strategies, and simulation-based dose selection, offer a framework to improve pre-eclampsia trial design. Future studies should integrate these approaches with biomarker-guided exposure-response analyses and prediction of fetal exposure throughout pregnancy to enhance therapeutic development, optimize maternal-fetal safety, and accelerate the identification of effective disease-modifying therapies for pre-eclampsia.