Disposition of betamethasone in parturient women after intramuscular administration.

Obstetrics & Gynecology

et al. 2006

OBJECTIVE-To study the pharmacokinetics of different betamethasone doses and preparations used to enhance fetal lung maturation in the maternal and fetal circulation of sheep and the adverse effects on fetal blood pressure.METHODS-Doses of 170 (n = 6) and 110 µg/kg (n = 6) betamethasone phosphate equivalent to 12 or 8mg, respectively, administered to a 70kg pregnant woman or 170 µg/kg (n = 6) of a depot formulation (50% betamethasone phosphate and 50% betamethasone acetate) were injected intramuscularly to chronically instrumented pregnant sheep.RESULTS-Both betamethasone preparations produced highest maternal concentrations after 15 min followed by an exponential decline with a t 1/2 of about 3 hours. The drug fell below the limit of detection at 8 to 12 hours. Betamethasone was first detectable in the fetal circulation at 1 hour, peaked at 3 hours, and decreased below the limit of detection at 8 hours independently of the dose or preparation. Maternal and fetal betamethasone concentrations achieved with the phosphate and acetate formulation were one half of those obtained with betamethasone phosphate, suggesting that very little betamethasone is released from the acetate within the first 8 hours when the effect on lung maturation is needed. Betamethasone led to a maximal increase of mean fetal blood pressure from 42 ± 1 to 51 ± 1 mm Hg (P<.05) and did not differ between the doses and preparations, although plasma concentrations showed a clear dose-concentration relationship.CONCLUSION-The doses of betamethasone used in obstetrics are supramaximal in terms of cardiovascular effects in sheep. Risk-benefit studies are needed to find the effective steroid dose with the least adverse effects.Administration of synthetic glucocorticoids to women in premature labor has a clearly proven clinical benefit in decreasing the incidence of respiratory distress syndrome and Although it has been shown in sheep that repeated treatments may be of benefit for the lung, 12 to our knowledge there has never been a study designed to examine a broad range of doses at the clinical level to determine the dose of maternal glucocorticoid that is optimal for the effects on the fetus in rodents, sheep, nonhuman primates or humans (PubMed, January 1966-January 2006; no language restrictions; search terms: antenatal or prenatal; glucocorticoids, steroids or betamethasone; dose or pharmacokinetics; lung or blood pressure). Recommendations 1 for dose and timing of treatments are mainly based on the study of Liggins and Howie 13 who chose the dose for clinical trials partly from the doses used in experiments with sheep. Retrospective data collected on mothers who received only a partial course of steroids, however, suggests that any exposure to an appropriate corticosteroid has beneficial effects on postnatal outcome. 14 The present study was designed to estimate the time course of maternal and fetal betamethasone concentrations after maternal exposure to two doses and two different betamethasone preparations frequently used clinically i...

Section: Discussionsupporting

confidence: 92%

Kinetics of Betamethasone and Fetal Cardiovascular Adverse Effects in Pregnant Sheep After Different Doses

Schwab

Coksaygan

Obstetrics & Gynecology

et al. 2006

“…Studies that have concluded that the acetate prodrug does not release betamethasone were short-duration studies that spanned 8 to 10 h (Petersen et al, 1984). Figure 2 demonstrates that, during this early time period, the pharmacokinetic profiles from the two formulations are virtually superimposable.…”

Section: Samtani Et Almentioning

confidence: 92%

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

Löhle²,

Grant³

et al. 2005

Drug Metab Dispos

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. ...

“…The human maternal BW is that of a 33-week pregnant woman whose betamethasone pharmacokinetic profile is reported in the literature (31). The human fetal BW for a 33-week conceptus is based on literature norms (34).…”

Section: Allometric Scaling Of Betamethasone Pharmacokineticsmentioning

confidence: 99%

“…Additional betamethasone data for the prodrug depot formulation in pregnant sheep and humans were extracted from the literature (5,30,31). Dexamethasone pharmacokinetic data after an intravenous injection of dexamethasone phosphate in pregnant rats were also published (19).…”

Section: Data Sourcesmentioning

confidence: 99%

Area/Moment and Compartmental Modeling of Pharmacokinetics During Pregnancy: Applications to Maternal/Fetal Exposures to Corticosteroids in Sheep and Rats

Schwab

Nathanielsz³

et al. 2004

Pharm Res