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Safety and pharmacokinetics of pravastatin used for the prevention of preeclampsia in high-risk pregnant women: a pilot randomized controlled trial.

ABSTRACT: BACKGROUND:Preeclampsia complicates approximately 3-5% of pregnancies and remains a major cause of maternal and neonatal morbidity and mortality. It shares pathogenic similarities with adult cardiovascular disease as well as many risk factors. Pravastatin, a hydrophilic, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitor, has been shown in preclinical studies to reverse various pathophysiological pathways associated with preeclampsia, providing biological plausibility for its use for preeclampsia prevention. However, human trials are lacking. OBJECTIVE:As an initial step in evaluating the utility of pravastatin in preventing preeclampsia and after consultation with the US Food and Drug Administration, we undertook a pilot randomized controlled trial with the objective to determine pravastatin safety and pharmacokinetic parameters when used in pregnant women at high risk of preeclampsia. STUDY DESIGN:We conducted a pilot, multicenter, double-blind, placebo-controlled, randomized trial of women with singleton, nonanomalous pregnancies at high risk for preeclampsia. Women between 12(0/7) and 16(6/7) weeks' gestation were assigned to daily pravastatin 10 mg or placebo orally until delivery. Primary outcomes were maternal-fetal safety and pharmacokinetic parameters of pravastatin during pregnancy. Secondary outcomes included rates of preeclampsia and preterm delivery, gestational age at delivery, birthweight, and maternal and cord blood lipid profile (clinicaltrials.gov identifier NCT01717586). RESULTS:Ten women assigned to pravastatin and 10 to placebo completed the trial. There were no differences between the 2 groups in rates of study drug side effects, congenital anomalies, or other adverse or serious adverse events. There was no maternal, fetal, or neonatal death. Pravastatin renal clearance was significantly higher in pregnancy compared with postpartum. Four subjects in the placebo group developed preeclampsia compared with none in the pravastatin group. Although pravastatin reduced maternal cholesterol concentrations, umbilical cord cholesterol concentrations and infant birthweight were not different between the groups. The majority of umbilical cord and maternal pravastatin plasma concentrations at the time of delivery were below the lower limit of quantification of the assay. Pravastatin use was associated with a more favorable pregnancy angiogenic profile. CONCLUSION:This study provides preliminary safety and pharmacokinetic data regarding the use of pravastatin for preventing preeclampsia in high-risk pregnant women. Although the data are preliminary, no identifiable safety risks were associated with pravastatin use in this cohort. This favorable risk-benefit analysis justifies using pravastatin in a larger clinical trial with dose escalation.

SUBMITTER: Costantine MM

PROVIDER: S-EPMC4884459 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Safety and pharmacokinetics of pravastatin used for the prevention of preeclampsia in high-risk pregnant women: a pilot randomized controlled trial.

Costantine Maged M MM Cleary Kirsten K Hebert Mary F MF Ahmed Mahmoud S MS Brown Linda M LM Ren Zhaoxia Z Easterling Thomas R TR Haas David M DM Haneline Laura S LS Caritis Steve N SN Venkataramanan Raman R West Holly H D'Alton Mary M Hankins Gary G

American journal of obstetrics and gynecology 20151223 6

<h4>Background</h4>Preeclampsia complicates approximately 3-5% of pregnancies and remains a major cause of maternal and neonatal morbidity and mortality. It shares pathogenic similarities with adult cardiovascular disease as well as many risk factors. Pravastatin, a hydrophilic, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitor, has been shown in preclinical studies to reverse various pathophysiological pathways associated with preeclampsia, providing biological plausibility for its use ...[more]

PMID: 26723196

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Project description:BackgroundPreeclampsia remains a major cause of maternal and neonatal morbidity and mortality. Biologic plausibility, compelling preliminary data, and a pilot clinical trial support the safety and utility of pravastatin for the prevention of preeclampsia.ObjectiveWe previously reported the results of a phase I clinical trial using a low dose (10 mg) of pravastatin in high-risk pregnant women. Here, we report a follow-up, randomized trial of 20 mg pravastatin versus placebo among pregnant women with previous preeclampsia who required delivery before 34+6 weeks' gestation with the objective of evaluating the safety and pharmacokinetic parameters of pravastatin.Study designThis was a pilot, multicenter, blinded, placebo-controlled, randomized trial of women with singleton, nonanomalous pregnancies at high risk for preeclampsia. Women between 12+0 and 16+6 weeks of gestation were assigned to receive a daily pravastatin dose of 20 mg or placebo orally until delivery. In addition, steady-state pravastatin pharmacokinetic studies were conducted in the second and third trimesters of pregnancy and at 4 to 6 months postpartum. Primary outcomes included maternal-fetal safety and pharmacokinetic parameters of pravastatin during pregnancy. Secondary outcomes included maternal and umbilical cord blood chemistries and maternal and neonatal outcomes, including rates of preeclampsia and preterm delivery, gestational age at delivery, and birthweight.ResultsOf note, 10 women assigned to receive pravastatin and 10 assigned to receive the placebo completed the trial. No significant differences were observed between the 2 groups in the rates of adverse or serious adverse events, congenital anomalies, or maternal and umbilical cord blood chemistries. Headache followed by heartburn and musculoskeletal pain were the most common side effects. We report the pravastatin pharmacokinetic parameters including pravastatin area under the curve (total drug exposure over a dosing interval), apparent oral clearance, half-life, and others during pregnancy and compare it with those values measured during the postpartum period. In the majority of the umbilical cord and maternal samples at the time of delivery, pravastatin concentrations were below the limit of quantification of the assay. The pregnancy and neonatal outcomes were more favorable in the pravastatin group. All newborns passed their brainstem auditory evoked response potential or similar hearing screening tests. The average maximum concentration and area under the curve values were more than 2-fold higher following a daily 20 mg dose compared with a 10 mg daily pravastatin dose, but the apparent oral clearance, half-life, and time to reach maximum concentration were similar, which is consistent with the previously reported linear, dose-independent pharmacokinetics of pravastatin in nonpregnant subjects.ConclusionThis study confirmed the overall safety and favorable pregnancy outcomes for pravastatin in women at high risk for preeclampsia. This favorable risk-benefit analysis justifies a larger clinical trial to evaluate the efficacy of pravastatin for the prevention of preeclampsia. Until then, pravastatin use during pregnancy remains investigational.

Project description:BackgroundThe prone position is rarely used in medical settings in pregnancy. There is no published information about the prone position in women with preeclampsia. This study examined the feasibility and acceptability of the prone position in pregnant women, and the short-term effect of the prone position on blood pressure (BP) in term healthy pregnant women and in women with preeclampsia.MethodsAfter ethics approval, written consent and trial registration (ACTRN:12615000160538 registered 18/02/2015, date of first participant enrolled 03/03/2015), 50 healthy term pregnant women and 15 women with preeclampsia had BP, heart rate (HR), oxygen saturation (SpO2), respiratory rate (RR), fetal heart rate (FHR) and comfort levels measured in two positions: left lateral, and prone. Measurements were after five minutes rest in each position.ResultsMean ± SD age, gestation and body mass index for healthy pregnant women was 33 ± 4.1 years, 38 ± 1.0 weeks and 27 ± 3.2 kg.m- 2 and for women with preeclampsia was 32 ± 4.7 years, 36 ± 3.4 weeks, 31 ± 5.6 kg.m- 2 respectively. No clinically significant changes occurred in healthy pregnant women in the prone position. Systolic BP was reduced in the prone position in women with preeclampsia (P = 0.019, mean difference - 6.6 mmHg, 95% confidence interval - 11.9 to - 1.3 mmHg). 33% of women with preeclampsia experienced a 10 mmHg or greater reduction in systolic BP in the prone position. 42% of healthy pregnant women and 47% of women with preeclampsia preferred the prone position to lateral.ConclusionsThis is the first study to examine the prone position in women with preeclampsia. For short periods of time the prone position is feasible and comfortable in pregnant women including those at term. The prone position may reduce systolic BP in women with preeclampsia without obvious adverse effects. Larger studies with women lying for longer periods in the prone position are required. Pregnancy should not be a contraindication to the prone position for short periods of time.Trial registrationACTRN:12615000160538.

Dataset Information

Safety and pharmacokinetics of pravastatin used for the prevention of preeclampsia in high-risk pregnant women: a pilot randomized controlled trial.

Publications

Safety and pharmacokinetics of pravastatin used for the prevention of preeclampsia in high-risk pregnant women: a pilot randomized controlled trial.

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