Pharmacokinetics and Pharmacodynamics of Intramuscular and Oral Betamethasone and Dexamethasone in Reproductive Age Women in India

Abstract

High-dose betamethasone and dexamethasone are standard of care treatments for women at risk of preterm delivery to improve neonatal respiratory and mortality outcomes. The dose in current use has never been evaluated to minimize exposures while assuring efficacy. We report the pharmacokinetics and pharmacodynamics (PDs) of oral and intramuscular treatments with single 6 mg doses of dexamethasone phosphate, betamethasone phosphate, or a 1:1 mixture of betamethasone phosphate and betamethasone acetate in reproductive age South Asian women. Intramuscular or oral betamethasone has a terminal half-life of 11 hours, about twice as long as the 5.5 hours for oral and intramuscular dexamethasone. The 1:1 mixture of betamethasone phosphate and betamethasone acetate shows an immediate release of betamethasone followed by a slow release where plasma betamethasone can be measured out to 14 days after the single dose administration, likely from a depo formed at the injection site by the acetate. PD responses were: increased glucose, suppressed cortisol, increased neutrophils, and suppressed basophils, CD3CD4 and CD3CD8 lymphocytes. PD responses were comparable for betamethasone and dexamethasone, but with longer times to return to baseline for betamethasone. The 1:1 mixture of betamethasone phosphate and betamethasone acetate caused much longer adrenal suppression because of the slow release. These results will guide the development of better treatment strategies to minimize fetal and maternal drug exposures for women at risk of preterm delivery.

Figure 1

Plasma concentration‐time profiles following 6 mg doses given i.m. of (a) dexamethasone phosphate (DexP), betamethasone phosphate (BetaP), and BetaP plus betamethasone acetate (BetaA) as semi‐log plots of geometric means ± 1 SD vs. time. The insert gives the concentration time profiles on a linear scale as arithmetic means ± SD. Frame (b) gives concentration‐time profiles following oral administration of 6 mg DexP and BetaP.

Figure 2

Pharmacodynamics of plasma glucose and cortisol following the steroid treatments. (a) Mean values for plasma glucose measured for the 24 hour baseline period and for 60 hours following treatment at hour 0. (b) Mean values for cortisol demonstrate the diurnal changes in cortisol for 24 hours prior to the steroid treatment at hour 0. All treatments caused severe adrenal suppression with variable times of recovery for measurements to 96 hours.

Figure 3

Pharmacodynamics of blood neutrophils, basophils, and CD3CD4 and CD3CD8 lymphocytes. Mean response curves giving the baseline measurements for the 24 hours before the 6 mg corticosteroid treatments given at hour 0. The treatments are color coded, with measurements to 96 hours. (a) Neutrophils, (b) Basophils, (c) CD3CD4 lymphocytes, and (d) CD3CD8 lymphocytes.

Figure 4

Bar graphs of median ± 25th–75th percentiles of rebound times (RTs) and relative potency using the Kaplan–Meier method to account for observations that are right censored due to a failure to rebound from the corticosteroid treatment effect prior to the last observation. Plus signs are used to indicate when there was too much censoring to determine the 75th percentile per the Kaplan–Meier method, and instead a lower bound is presented, imputed with the final observations of the individually censored subjects. (a) RTs were calculated as the time (hours) that the corticosteroid treatment effect returned to the time‐matched baseline value, calculated for each individual measurement. (b) Relative potency was calculated as the change from baseline in the area under the exposure curve (ΔAUEC) from hour 0 to the RT, normalized to the median value for DexP IM. To enhance readability, both increases and decreases in ΔAUEC are shown as positive numbers. Glucose and neutrophils increased with corticosteroid exposure, whereas cortisol, basophils CD₃CD₄, lymphocytes, and CD₃CD₈ lymphocytes decreased.