200. Clinical trial of metformin to treat preterm preeclampsia: pharmacokinetics and biomarker studies

Abstract

Introduction Metformin is a potential therapeutic for preeclampsia as it decreases sFlt-1 and soluble endoglin and rescues endothelial dysfunction. Metformin pharmacokinetics in preeclampsia, where there is increased renal clearance and proteinuria, has not been established. Objective/Hypothesis To evaluate metformin XR (extended release) pharmacokinetics in preterm preeclampsia, obtain data on pregnancy prolongation and circulating levels of biomarkers associated with endothelial dysfunction. Methods 15 women with preterm preeclampsia were treated with 1.5 g metformin XR twice daily. Pharmacokinetic sampling was performed on day 1 at 2,4,5,6,7,8,24 h, and concentrations measured using liquid chromatography-tandem mass spectrometry. Given steady state is reached at 24–48 h, trough concentrations were measured at day 1 and 5 to assess the increase in Cmin over time. Plasma was taken twice weekly and biomarkers of endothelial dysfunction measured. Results Gestation at recruitment ranged from 27 to 31 weeks, and median prolongation was 11.5 days [IQR 5.8–23.8]. Pharmacokinetic studies confirmed excellent circulating levels at 0–12 h exposure, with Cmax [median (IQR)] 1.6 (1.3–1.9) mg/l, AUC 0–12 11.7 (8.9–13.5) mg.h/l and AUC 0-infinity 17.0 (10.7–36.6) mg.h/l. Day 1 and 5 trough concentrations were 0.55 (0.34–1.22) mg/l and 0.01 (0.01–0.70) mg/l suggesting steady state exposure is similar to day 1. Umbilical cord blood:plasma ratios taken 4 (3–9.5) hours after dosing were 0.67 (0.2–0.86). None of the following circulating biomarkers increased across pregnancy among those who remain undelivered: sFlt1, soluble endoglin, Vascular Cell Adhesion Molecule 1, Endothelin-1 and placental growth factor. Discussion 1.5 g of metformin XL twice daily in preterm preeclampsia resulted in at least the same exposure as 2 g daily in healthy controls, despite pregnancy and preeclampsia related changes. Metformin potentially stabilised levels of circulating biomarkers of endothelial dysfunction. Randomised trials to treat preterm preeclampsia should be performed.