Comprehensive evaluation of the safety and utility of pravastatin in prevention of preeclampsia in high-risk pregnant women

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ABSTRACT—Clinical Project Preeclampsia (PE) affects 3% to 8% of pregnant women and remains a major cause of morbidity and mortality. With no effective therapy for PE, the only approach to prevent maternal morbidity is delivery. Due to the similarities between PE and cardiovascular disease, we and others have demonstrated the ability of pravastatin (PRA) to reverse several pathophysiologic pathways and phenotypic features of PE. The labeling of PRA as category X is predominantly due to the absence of an indication for its use in pregnancy, as data from experimental animal models and cohorts of pregnant women exposed to PRA early in pregnancy did not support the teratogenicity claims of a category X medication. Recently, as a site in the NICHD-OPRU network and after obtaining an IND from the FDA, we completed a pilot, double-blinded, randomized clinical trial (RCT) of pregnant women at high risk of PE, randomized to 10 mg PRA or placebo. The study revealed favorable maternal-fetal safety and pharmacokinetic (PK) profiles of PRA in this population. The completed pilot trial utilized the lowest dose of PRA (10 mg) allowed in the IND, and our proposed investigation in this application will evaluate PRA at a higher dose (20 mg) already approved by the FDA IND. Our hypothesis is that pravastatin, when given to pregnant women at high risk of PE, exhibits favorable maternal-fetal safety, pharmacodynamics (PD), and PK Profiles. We are proposing a double-blind, placebo- controlled RCT of 100–120 pregnant women at high risk for PE to investigate the following specific aims: (1) determine the maternal-fetal safety profile of PRA during pregnancy, (2) determine whether early prophylactic treatment with PRA in high-risk women reverses the angiogenic imbalance associated with PE, (3) determine the PK of PRA and the formation of its metabolites during pregnancy (compared to the postpartum period), and (4) determine the effects of SNPs in genes encoding uptake and efflux transporters and sulfotransferase enzymes on maternal exposure to PRA. The data obtained on safety, PK parameters, and PD will be compared between the different doses to determine which dose results in the most significant PD effect and the most favorable safety profile. This determination will provide the framework required for the implementation of a larger clinical trial to determine PRA’s ability to prevent PE.