Dipyridamole for Early-Onset Preeclampsia: A Pilot Study of Feasibility, Pharmacokinetics, and Biological Effects

Study Type: Single-center, open-label, pilot interventional study evaluating an approved medication (dipyridamole) in an off-label indication.

Background and Rationale:

Early-onset preeclampsia (PE), typically presenting before 34 weeks of gestation, is the most severe phenotype of hypertensive pregnancy disease and a leading cause of maternal and perinatal morbidity. Once clinically established, there is no disease-modifying therapy; management relies almost exclusively on close surveillance and timely delivery, frequently resulting in extreme prematurity. Early-onset PE is increasingly recognized as a primarily placental disorder, driven by defective placentation, chronic ischemia-reperfusion injury, progressive trophoblast damage, and maladaptive stress responses, in contrast to late-onset disease, which is more strongly influenced by maternal cardiovascular and metabolic susceptibility.

Prior laboratory research identified ferroptosis, a form of regulated cell death driven by iron-catalyzed peroxidation of membrane phospholipids, as a key mechanism of placental injury in early-onset PE. Human trophoblasts were shown to be uniquely vulnerable to ferroptosis due to their high iron content and intense oxidative metabolism. Using redox phospholipidomics, preeclamptic placentas were shown to accumulate specific hydroperoxy-phosphatidylethanolamine species characteristic of ferroptotic cell death; inducing ferroptosis in placental explants drove sFlt-1 release, and ferroptosis inhibitors reversed both tissue damage and sFlt-1 secretion. Multiple independent groups have since confirmed ferroptosis as a driver of placental injury in preeclampsia.

A high-throughput robotic screen of over 6,500 drugs and compounds, designed to identify pregnancy-safe ferroptosis inhibitors in primary human trophoblast cultures, identified dipyridamole as one of the most potent candidates (EC50 = 0.146 μM), acting independently of its known phosphodiesterase-inhibitory pharmacology. In preeclamptic placental explants, dipyridamole treatment led to a marked and reproducible reduction in sFlt-1 release, a central pathogenic mediator of the maternal syndrome.

From a safety perspective, dipyridamole has an established pregnancy safety record. It is classified as FDA Pregnancy Category B, and a Cochrane meta-analysis of antiplatelet agents in pregnancy confirmed that this drug class is safe and reduces preeclampsia, preterm birth, and small-for-gestational-age births.

Study Rationale Summary:

This study combines a defined molecular target (ferroptosis) with circulating biomarkers (sFlt-1/PlGF ratio) and Doppler parameters that can objectively track placental stress and treatment response, in a population with biomarker-confirmed placental dysfunction expected to deteriorate without intervention. If successful, this pilot would provide preliminary evidence supporting further evaluation of a disease-modifying therapy for established early-onset preeclampsia.

Study Design:

This is a prospective, single-center, open-label pilot study using a sequential, fixed dose-escalation design, evaluating the feasibility and clinical implementation of dipyridamole treatment in women with early-onset preeclampsia, including pharmacokinetic assessment, within standard obstetric care. The study is intentionally designed as a non-randomized pilot; its purpose is not to establish definitive clinical efficacy, but to assess real-world implementability, characterize pharmacokinetics and tolerability during pregnancy, and generate biological and clinical signals to inform the design of a subsequent randomized controlled trial.

Enrollment proceeds through a staged sentinel design: the first participant is enrolled and treated alone, with no further enrollment until she has completed treatment, delivered, and been assessed through the first 24 hours postpartum, and until the independent Safety Monitoring Committee has reviewed the complete safety data and recommended proceeding. Following a favorable review, two additional participants are enrolled, with a second safety gate before enrollment continues toward the planned sample size. This staged approach allows accumulated safety experience to govern each expansion of exposure.

All participants receive dipyridamole in addition to standard clinical management for early-onset preeclampsia, provided in accordance with established international and national guidelines. Study participation does not modify, delay, or replace any component of standard clinical care; decisions regarding antihypertensive therapy, treatment escalation, or delivery timing are made exclusively on clinical grounds by the treating team, independent of study participation. The dose-escalation scheme is fixed and identical for all participants; dosing is not individualized and accelerated escalation is not permitted.

Pharmacokinetic Sampling:

Pharmacokinetic blood samples are drawn, whenever possible, from the participant's existing indwelling intravenous catheter to minimize discomfort. Sparse sampling is performed during the dose-escalation phase, and after reaching the target dose each participant undergoes one intensive pharmacokinetic profiling day, provided maternal and fetal conditions allow a stable sampling window.

Safety Oversight:

Safety oversight is provided by an independent Safety Monitoring Committee comprising five members: an external maternal-fetal medicine specialist, a neonatologist, a hematologist with expertise in coagulation and bleeding risk, a specialist in internal medicine and clinical pharmacology, and an independent epidemiologist/biostatistician. The Committee is independent of the conduct of the study and reviews all serious adverse events, all events meeting a stopping-rule trigger, and cumulative safety data. It governs the staged sentinel enrollment gates and conducts scheduled safety reviews after the first 5 and first 10 participants complete treatment, in addition to any ad hoc reviews triggered by safety events. Final clinical decisions remain with the treating team, with maternal and fetal safety taking priority.

Postpartum follow-up continues to six weeks and includes documentation of adverse events, blood pressure and antihypertensive requirement, readmission, postpartum hemorrhage, infection or surgical complication, and hemoglobin.

• Peak Plasma Concentration (Cmax) of Dipyridamole [Срок оценки: Pre-dose through 6-8 hours post-dose on the intensive PK profiling day (after reaching target dose or highest tolerated dose)]
• Incidence of Dipyridamole-Related Adverse Events [Срок оценки: From first drug administration until six weeks postpartum]
• Change in Serum Soluble fms-Like Tyrosine Kinase-1 (sFlt-1) [Срок оценки: Daily for the first 7 days, then every 72 hours until delivery]
• Change in Maternal Blood Pressure [Срок оценки: From treatment initiation until delivery (estimated 1-5 weeks)]
• Pregnancy Latency from Treatment Initiation to Delivery [Срок оценки: From first dose through delivery (estimated 1-5 weeks)]
• Uterine Artery Pulsatility Index (UtA-PI) [Срок оценки: From enrollment through delivery (estimated 1-5 weeks)]
• Trough Plasma Concentration (Ctrough) of Dipyridamole [Срок оценки: From treatment initiation through delivery (estimated 1-5 weeks)]
• Area Under the Plasma Concentration-Time Curve (AUC) of Dipyridamole [Срок оценки: Pre-dose through 6-8 hours post-dose on the intensive PK profiling day]
• Apparent Oral Clearance (CL/F) of Dipyridamole [Срок оценки: From treatment initiation through the intensive PK profiling day (estimated 1-5 weeks)]
• Terminal Elimination Half-Life (t½) of Dipyridamole [Срок оценки: Calculated from PK samples collected on the intensive PK profiling day (up to 6-8 hours post-dose)]
• Need for Initiation or Escalation of Antihypertensive Therapy [Срок оценки: From treatment initiation until delivery (estimated 1-5 weeks)]
• Overall Antihypertensive Medication Burden [Срок оценки: From treatment initiation until delivery (estimated 1-5 weeks)]