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.

FIGURE 1

Betamethasone clearance (left) and AUC_0‐24h (right) for pregnant women without early‐onset pre‐eclampsia (w/o‐eoPE) and with early‐onset pre‐eclampsia (eoPE), concentrations based on maternal blood samples. AUC_0‐24h: area under the curve within 24 h after first dose. The median betamethasone clearance of patients w/o eoPE is 15.8 L/h, the median betamethasone clearance of patients with eoPE is 9.35 L/h. The median betamethasone AUC_0‐24h of patients w/o eoPE is 584 ng h/mL (range 394–751 ng h/mL), the median betamethasone AUC_0‐24h of patients with eoPE is 709 ng h/mL (range 609–919 ng h/mL).

FIGURE 2

The visual predictive check result of the betamethasone from maternal blood samples (pregnant women without early‐onset pre‐eclampsia [w/o eoPE] and with early‐onset pre‐eclampsia [eoPE]) to show how the trend of observation concentration (solid line: concentration median trend line, dashed line: concentration P5 (5%) and P95 (95%) fall within the model parameter simulated trend (red area: median simulation; blue shaded area: P5 and P95 of the simulation) within 95% confidence interval. The median trend line of the observed data falls within the corresponding simulations while the P5 and P95 have 4 points that slightly fall outside of the simulation area. The X‐axis presents the time (in h) and the Y‐axis the concentration of betamethasone (in μg/L).

FIGURE 3

Simulation of betamethasone exposure in pregnant women with early‐onset pre‐eclampsia (eoPE) and without early‐onset pre‐eclampsia (w/o eoPE). The simulations are based on a standard patient (height of 165 cm, weight of 68 kg, with or without eoPE) that received 2 doses of 12 mg betamethasone once every 24 h for a total of 2 doses and up until 72 h after the final dose. The median concentrations are used to plot the simulations. The X‐axis presents the time (in h) after the first dose and the Y‐axis the concentration of betamethasone (in μg/L).

FIGURE 4

Betamethasone is transferred and metabolized by the placenta. A, B and C depict the data from 3 ex vivo placenta perfusion experiments with 1336 nmol/L betamethasone in the maternal circulation at the start of the experiment (t = 0). In these figures, the maternal circulation is displayed as closed circles and the foetal circulation is displayed as open circles. (A) Betamethasone detected in the maternal and foetal circulations. (B) 11‐ketobetamethasone detected in the maternal and foetal circulations. (C) Absence of 6β‐hydroxybetamethasone in the maternal and foetal circulations. (D) Healthy (n = 4) and early‐onset pre‐eclampsia (n = 4) placental explants metabolize betamethasone into 11‐ketobetamethasone. The 11‐keto‐betamethasone : betamethasone ratios are normalized to the amount of tissue (g) in each experiment. Data are depicted as mean ± standard deviation.

FIGURE 5

Umbilical cord blood concentrations of betamethasone, 11‐keto‐betamethasone and 6β‐hydroxybetamethasone (A‐C) and the 11‐keto‐betamethasone : betamethasone ratio (D) and 6β‐hydroxybetamethasone/betamethasone ratio (E) in patients without early‐onset pre‐eclampsia (black circles) and with early‐onset pre‐eclampsia (red squares).