Pharmacokinetics of betamethasone in pre-eclampsia: An in vivo and ex vivo study

Abstract

Aims: To enhance understanding of betamethasone and its metabolites' pharmacokinetics in pregnancy, specifically early-onset pre-eclampsia, through a population pharmacokinetic model. Additionally, to investigate the placental metabolism and transfer of betamethasone and its main metabolites.

Methods: A prospective, single-centre pharmacokinetic study was conducted in pregnant women (n = 28) with imminent preterm birth treated with intramuscular betamethasone. Betamethasone serum concentrations were determined from serial venous blood samples (n = 194). Placental transfer and metabolism were studied using ex vivo human placental perfusion (healthy term; n = 3) and placental explant experiments (healthy term, n = 4; early-onset pre-eclampsia, n = 4). Additionally, placental mRNA expression of CYP3A4, CYP3A7, 11β-hydroxysteroid dehydrogenase (HSD) 1 and 11β-HSD2 were quantified in healthy and early-onset pre-eclampsia placentas.

Results: The population pharmacokinetic model was best described by a 2-compartment nonlinear mixed effects model. Betamethasone clearance in early-onset pre-eclamptic women was 60% lower of that observed in women without pre-eclampsia (9.35 vs. 15.78 L/h), resulting in a 40% median increase in maternal betamethasone exposure (1567 vs. 1114 ng h/mL). Ex vivo experiments showed placental transfer of betamethasone to the foetal circulation (foetal-to-maternal ratio 0.76 ± 0.05 [in a perfused placental cotyledon]). The placenta only converted betamethasone into 11-ketobetamethasone, with similar ratios in early-onset pre-eclampsia and healthy placental explants (3.0 ± 2.2 vs. 1.4 ± 0.4 per mg tissue, P = .27). The expression of 11β-HSD1 mRNA was lower in early-onset pre-eclampsia placentas (P = .015), while placental CYP3A7 and 11β-HSD2 mRNA expression were similar.

Conclusion: Women with early-onset pre-eclampsia have elevated betamethasone exposure. Betamethasone transfers freely into the foetal circulation, with placental metabolism resulting only in 11-ketobetamethasone. Decreased placental 11β-HSD1 expression may play a role in increased betamethasone exposure in early-onset pre-eclampsia.

Keywords: antenatal corticosteroids; betamethasone; population pharmacokinetics; preterm birth; pre‐eclampsia.