Betamethasone Pharmacokinetics After Two Prodrug Formulations in Sheep: Implications for Antenatal Corticosteroid Use

Abstract

ABSTRACT:Maternal administration of betamethasone to enhance fetal lung maturation for women who threaten preterm labor is common clinical practice. However, recommendations regarding the choice of betamethasone formulations for perinatal use are vague. The disposition of betamethasone from two commonly used antenatal formulations is poorly understood. We therefore designed a study to capture the true pharmacokinetic profiles of betamethasone from these fast acting and dual-release formulations. Betamethasone in sheep plasma was measured by a newly designed, highly sensitive liquid chromatography/tandem mass spectrometry assay after intramuscular injection (n ‫؍‬ 4) of 0.25 mg/kg betamethasone phosphate and 0.5 mg/kg betamethasone phosphate/acetate formulations. Compartmental modeling was performed using the ADAPT II program. Betamethasone pharmacokinetics could be captured for 24 h for the phosphate and for 5 days for the phosphate/acetate formulations. The phosphate formulation profile had the appearance of a traditional Bateman function with a terminal half-life of 4 h, whereas the phosphate/acetate formulation produced a biexponential decline with a terminal half-life of 14 h. The latter is much longer than is commonly reported and has been missed in the literature due to assay limitations. Extrapolations to humans indicate that although both formulations might have similar therapeutic indices, the dual formulation might be associated with a lower safety profile. In light of this newly identified long terminal half-life for the betamethasone dual formulation, dosing practices for betamethasone in pregnancy need to be reassessed.Preterm birth occurs in about 10% of pregnancies, and complications associated with prematurity, especially respiratory distress syndrome, are the leading cause of mortality in prematurely born infants (NIH Consensus Panel, 1995). Betamethasone is administered maternally to enhance fetal lung maturation in women who threaten preterm labor during 24 to 34 weeks gestation. The National Institutes of Health recommends administration of two maternal intramuscular injections of 12-mg betamethasone 24 h apart for this condition. Although the doses of betamethasone are stated, the exact formulation recommendation is not clear. Betamethasone is available as a fast releasing phosphate ester prodrug formulation and as a dual acting suspension formulation containing phosphate and acetate ester prodrugs. Both formulations have been tested in clinical trials and have been shown to be efficacious in producing precocious fetal lung maturation (Liggins and Howie, 1972;Gamsu et al., 1989). However, there is controversy regarding the betamethasone-releasing properties of the acetate prodrug, and a recent meta-analysis suggests that this prodrug is probably of little therapeutic benefit for antenatal use (Jobe and Soll, 2004). Although the release properties of the acetate prodrug have been questioned, long-duration studies looking at the release pattern of betamethasone from this prodrug do not exist. ...

Betamethasone for lung maturation: testing dose and formulation in fetal sheep

“…Betamethasone given to the fetus is cleared from the fetus 4 times faster than it lost from the fetus when the ewe is treated (19). The terminal half-life of Beta-PO 4 in the ewe is about 4h while the value recently reported for the Beta-PO 4 -Beta-Ac mixture is 14h, long relative to Beta-PO 4 but much shorter than reported in standard texts (20). While the different preparations of Beta will have effects while the drug is in the circulation, this corticosteroid binds tightly to receptors and can have prolonged effects that extend well beyond plasma availability.…”

Betamethasone Attenuates Oxidant Stress in Endothelial Cells from Fetal Lambs with Persistent Pulmonary Hypertension

“…The concentration of betamethasone we added to the PAEC for in vitro studies is twice the plasma concentrations measured in pregnant sheep following a single dose of 0.25 mg/kg (20). Since clinical use of this drug consists of two doses, we chose to add twice the measured concentration initially without addition of subsequent doses during the 48-h period.…”

“…The medium was then replaced with either 20% FBS-DMEM or 20% FBS-DMEM with betamethasone (Sigma Chemical Co.) at a concentration of 400 ng/mL (10 -6 M) for 48 h. The concentration of betamethasone in media is based on plasma concentrations measured in pregnant sheep plasma (20) following a single injection of 0.25 mg/kg (approximately 12 mg for a 50-kg sheep) and are 10 -20 fold higher than concentrations measured in fetal lambs (21).…”

Modeling Glucocorticoid-Mediated Fetal Lung Maturation: I. Temporal Patterns of Corticosteroids in Rat Pregnancy

“…DEX was measured in maternal/fetal plasma, plasma ultrafiltrate, and fetal tissue. Plasma DEX concentrations were determined by a highly sensitive and specific solid phase extraction liquid chromatography-tandem mass spectrometry method as described previously (Samtani et al, 2005). The limit of quantitation was 0.25 nM, and the interday and intraday coefficients of variation were less than 20%.…”

“…The following criteria were defined, which are thought to be critical in obtaining optimal steroid exposure. 1) The dissociation constant for the fetal lung glucocorticoid receptor is considered to be an efficacy threshold (Samtani et al, 2005). Maintaining fetal free plasma concentrations above this threshold of 4.7 nM (Ballard et al, 1978) in rat might be conducive to mediating fetal lung maturational effects.…”