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What is the half life of betamethasone. Pharmacokinetics of betamethasone in healthy adults after intravenous administration
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 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.
The 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 comparable for betamethasone and dexamethasone, but with longer times to return to baseline for betamethasone.
The 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. 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.
Substances Glucocorticoids betamethasone acetate phosphate betamethasone sodium phosphate Dexamethasone Betamethasone.
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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 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.
The 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 comparable for betamethasone and dexamethasone, but with longer times to return to baseline for betamethasone.
The currently accepted dosage of betamethasone was determined by Liggins and Howie in the s; since that time, pregnant women at risk for preterm birth have been administered a fixed dosage of betamethasone, regardless of gestational age, maternal body mass index, and the presence of a singleton or multiple gestation [ 8 ]. Although betamethasone treatment reduces mortality and morbidity in general [ 9 ], its effect for a particular woman may be unpredictable, and varying outcomes between two preterm neonates with similar obstetrical background born at a similar gestational age after treatment with betamethasone may often be observed.
Moreover, among multiple pregnancies, the benefit of betamethasone is uncertain [ 10 , 11 ]. For that reason the optimal dosage for betamethasone in terms of benefit and safety is still unknown.
To the best of our knowledge, the relationship between betamethasone concentration and perinatal outcome has not been reported. In part, this may be due to an absence of a reliable method for measuring serum betamethasone concentrations. In view of that, we aimed in this study to assess the ability of a specific ELISA kit to measure the concentrations of betamethasone in maternal serum and to examine the trend of sequential measurements in maternal serum after a complete course of betamethasone for lung maturity.
This prospective study was held at a university teaching medical center between July and April Pregnant women between 24 weeks 0 days and 33 weeks 6 days of gestation, had singleton gestation, and received a complete course of betamethasone due to threatened preterm birth were included.
Women who received an incomplete course of betamethasone because of failure to delay delivery or who received corticosteroids for other reasons during pregnancy, had multiple gestations, or fetal malformations diagnosed in the antepartum period were excluded from the study.
In order to examine whether betamethasone levels are measurable and in order to examine the dynamics of betamethasone concentrations against time from treatment, blood samples were drawn from each participating woman at five time points: immediately before administering the betamethasone baseline ; at 36 hours after the first dose; at 48 hours after the first dose; at 72 hours after the first dose, and 5 to 7 days after the first dose, given that a preterm birth did not occur earlier.
These consecutive measurements were chosen in order to examine whether the trend of concentrations acted comparably to the anticipated clinical effect of betamethasone, which is best achieved within 7 days from the initial dose [ 9 ].
This kit, originally designed for urine, tissue, and serum samples in the veterinary field, was evaluated in our laboratory for use with human samples. Evaluation included precision, repeatability, linearity, and analytical sensitivity lower limit of detection. Those parameters were analyzed by spiking betamethasone provided with the kit and the same generic betamethasone that was administered to women into a pool of human sera. According to linearity range obtained in the evaluation, study samples were diluted accordingly in order to be measured within this range.
The present study was approved by the ethics committee of Emek Medical Center in compliance with the Helsinki declaration. Signed consent was obtained from each of the participating women before receiving the first betamethasone injection.
The mean and standard deviation of the betamethasone levels from all samples were calculated. The Friedman test was used to determine whether there were significant differences between betamethasone concentrations. For continuous variables, the Student t -test was implemented. SAS 9. A total of eight women were approached and consented. Three women delivered before receiving a complete course of betamethasone and for that reason they were excluded.
Overall, five women A to E received a complete course of betamethasone and were included in the study. Demographic and obstetric parameters are presented in Table 1. Base line and last measurements of woman E were not performed; the first was due to technical issues and the last due to the fact that she delivered before the scheduled examination.
Among all women, two delivered preterm, woman B and woman E Table 1. Woman B delivered at 30 weeks of gestation, 3 weeks after betamethasone administration. Betamethasone concentration 48 hours after the first dose was 0.
The neonate developed respiratory distress syndrome. Woman E delivered at 29 weeks of gestation, less than a week after betamethasone administration.
Betamethasone concentration 48 hours after the first dose was 1. The neonate did not develop respiratory distress syndrome. The other 3 women delivered at term. None of the neonates developed intraventricular hemorrhage or necrotizing enterocolitis. As shown in Fig. Among the measurements performed for each woman, the concentration was highest 36 hours after the first dose of betamethasone.
The concentration diminished gradually to a level close to the baseline at the 5 th measurement performed 5 to 7 days after the first dose of betamethasone. Although the trend of sequential measurements was similar for the five women, there were obvious variations at each time point Fig.
Trends of the sequential betamethasone concentration measurements of the 5 women included in the study. Calculated half-life of betamethasone differed according to the time elapsed from its administration Table 2. Mean half-life after 36 to 48 hours from administration The evaluation of betamethasone measurement kit performance demonstrated a high precision for spiked betamethasone in the human sera pool: average coefficient of variation of 3.
Analytical sensitivity lower limit of detection was 0. In this study we were able to measure betamethasone concentrations in the serum of pregnant women with the use of corticosteroid ELISA kit. Among the measurements performed for each woman, the concentration was highest at 36 hours after the first dose of betamethasone followed by a gradual decrease to a level close to the baseline at the 5 th measurement at 5 to 7 days.
The trend of sequential measurements performed similarly between all women; however the concentration varied at each time point between the five women. The near to baseline concentration at 5 to 7 days is similar to the described perinatal clinical effect that is best achieved within 7 days after drug administration [ 9 ]. The National Institutes of Health and the American College of Obstetricians and Gynecologists recommend routine glucocorticoid administration to women at risk for preterm birth between 24 and 34 weeks gestation to accelerate fetal lung maturation and to decrease the incidence of other neonatal morbidity and mortality related to prematurity [ 7 , 12 ].
When betamethasone is administered, the recommended regimen is two doses, 12 mg each, given intramuscularly 24 hours apart [ 7 , 12 ]. Although betamethasone treatment reduces mortality and morbidity in general, its effect on a particular woman is usually unpredictable. The current dosage of betamethasone was determined by Liggins and Howie during the s, and since then a fixed dosage is administered to all pregnant women regardless of gestational age, maternal body mass index, and whether a singleton or multiple gestation is present [ 8 ].
Additionally, betamethasone rapidly crosses the placenta [ 13 ]. Its administration to the pregnant mother inevitably exposes the fetus to glucocorticoid concentrations that may be inappropriate for the current stage of fetal development [ 14 ].
High blood pressure [ 15 ], reduced head circumference at birth [ 16 ], and reduced brain weight in monkey fetuses [ 17 , 18 ] are among the several adverse effects reported after glucocorticoid given to enhance fetal lung maturity. In view of that, the optimum betamethasone dosage and concentration in terms of benefit and safety to the developing fetus at any gestational age has not been established.
Loehle et al. Their data showed that half the normal clinical dose, adjusted for weight, may be functionally adequate [ 14 ]. On the other hand, Ballabh et al. They reported that the reasons are due to shorter half-life and greater clearance of betamethasone in twin pregnancy than in singleton pregnancy.
This may be attributed to the presence of two fetoplacental units in twins, which causes greater metabolism of betamethasone than in singletons [ 19 ], or a dilution effect due to the increased maternal blood volume and total body water [ 20 ]. In contrast to the previous studies we show that there is a variation in the concentrations among women with singleton pregnancies and a fixed dosage, whether smaller or larger than the acceptable regimen, may not be sufficient to reduce perinatal complications among all women.
The half-lives of betamethasone concentration found in the current study differ from the fixed 9. This may be due to imprecision in the technique used to measure betamethasone concentrations. Ballabh et al. Additionally, and compared to their results, two different half-lives were noted in the current study. Sahin et al. This is due to the fact that the systemic concentration time profile for most drugs is best described by a multi-exponential function, thereby yielding more than one half-life to describe the drug.
The choice of a single appropriate half-life value for such drugs is unclear [ 21 ]. This may also be explained with the two-compartment model that adds a peripheral compartment to the one-compartment model.
The peripheral compartment represents the opportunity for a drug to leave the plasma and enter other tissues. Among pregnant women, a third compartment may be present — the fetoplacental.
Drugs transfer to the fetus across the placenta and elimination from the fetus is by diffusion back to the maternal compartment. Moreover, the fetus plays an important role in the equilibrium of a compound because the fetus swallows amniotic fluid and urinates; there is a sort of drug recirculation within the fetal compartment along with the transfer back to maternal blood [ 22 ].
This may explain the existence of more than one half-life found in the current study. The results of the current study do not provide evidence as to the precise dosage of betamethasone that needs to be administered; the minimum betamethasone dosage that would be clinically effective is yet to be determined.
Basic pharmacologic principles suggest that the drug concentration in maternal serum may determine the fetal response and perinatal outcome and, as such, the optimal treatment regimen. Given that, the results of the current study may pave the way for future studies that could determine the optimum concentration and, accordingly, the dosage of betamethasone by investigating the minimum concentration that would be clinically effective to positively affect perinatal outcome.
Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med. Article Google Scholar. Preterm delivery. Article PubMed Google Scholar. Hack M, Dandruff AA. Early Hum Dev.
Reproductive Biology and Endocrinology volume 14Article number: 7 Cite this article. Metrics details. The association between maternal serum concentration of betamethasone given for fetal lung maturity and perinatal outcome has not been investigated. This may be due to an absence of a reliable method for measuring serum betamethasone concentrations.
We aimed in the current study to assess the feasibility of a specific ELISA kit to measure the concentrations of betamethasone in maternal serum and to examine the trend of sequential measurements after a course of betamethasone for fetal lung maturity. Pregnant women at risk for preterm birth who received betamethasone between 24 and 34 weeks of gestation were prospectively included.
Serum concentrations were determined before administering betamethasone baselineand 36 hours, 48 hours, 72 hours, and 5 to 7 days after the 1 st dose. The Friedman test was used to test whether there were significant differences between the measurements. Five singleton pregnancies were included. Using the ELISA kit, betamethasone concentration in maternal serum samples was obtained for all women.
Serum concentration varied at each time point between the five women but similar trend was observed. Additionally, these premature infants are at high risk for acute medical complications including respiratory distress syndrome, intraventricular hemorrhage, and necrotizing enterocolitis [ 23 ].
Subsequent randomized controlled trials, which demonstrated reduced perinatal mortality and morbidity, particularly respiratory distress syndrome, led to a change in antenatal care, and antenatal betamethasone therapy has become a standard of care in the majority of medical centers worldwide [ 67 ].
The currently accepted dosage of betamethasone was determined by Liggins and Howie in the s; since that time, pregnant women at risk for preterm birth have been administered a fixed dosage of betamethasone, regardless of gestational age, maternal body mass index, and the presence of a singleton or multiple gestation [ 8 ].
Although betamethasone treatment reduces mortality and morbidity in general [ 9 ], its effect for a particular woman may be unpredictable, and varying outcomes between two preterm neonates with similar obstetrical background born at a similar gestational age after treatment with betamethasone may often be observed. Moreover, among multiple pregnancies, the benefit of betamethasone is uncertain [ 1011 ].
For that reason the optimal dosage for betamethasone in terms of benefit and safety is still unknown. To the best of our knowledge, the relationship between betamethasone concentration and perinatal outcome has not been reported. In part, this may be due to an absence of a reliable method for measuring serum betamethasone concentrations.
In view of that, we aimed in this study to assess the ability of a specific ELISA kit to measure the concentrations of betamethasone in maternal serum and to examine the trend of sequential measurements in maternal serum after a complete course of betamethasone for lung maturity. This prospective study was held at a university teaching medical center between July and April Pregnant women between 24 weeks 0 days and 33 weeks 6 days of gestation, had singleton gestation, and received a complete course of betamethasone due to threatened preterm birth were included.
Women who received an incomplete course of betamethasone because of failure to delay delivery or who received corticosteroids for other reasons during pregnancy, had multiple gestations, or fetal malformations diagnosed in the antepartum period were excluded from the study. In order to examine whether betamethasone levels are measurable and in order to examine the dynamics of betamethasone concentrations against time from treatment, blood samples were drawn from each participating woman at five time points: immediately before administering the betamethasone baseline ; at 36 hours after the first dose; at 48 hours after the first dose; at 72 hours after the first dose, and 5 to 7 days after the first dose, given that a preterm birth did not occur earlier.
These consecutive measurements were chosen in order to examine whether the trend of concentrations acted comparably to the anticipated clinical effect of betamethasone, which is best achieved within 7 days from the initial dose [ 9 ]. This kit, originally designed for urine, tissue, and serum samples in the veterinary field, was evaluated in our laboratory for use with human samples. Evaluation included precision, repeatability, linearity, and analytical sensitivity lower limit of detection.
Those parameters were analyzed by spiking betamethasone provided with the kit and the same generic betamethasone that was administered to women into a pool of human sera. According to linearity range obtained in the evaluation, study samples were diluted accordingly in order to be measured within this range. The present study was approved by the ethics committee of Emek Medical Center in compliance with the Helsinki declaration.
Signed consent was obtained from each of the participating women before receiving the first betamethasone injection. The mean and standard deviation of the betamethasone levels from all samples were calculated. The Friedman test was used to determine whether there were significant differences between betamethasone concentrations. For continuous variables, the Student t -test was implemented. SAS 9. A total of eight women were approached and consented.
Three women delivered before receiving a complete course of betamethasone and for that reason they were excluded. Overall, five women A to E received a complete course of betamethasone and were included in the study. Demographic and obstetric parameters are presented in Table 1. Base line and last measurements of woman E were not performed; the first was due to technical issues and the last due to the fact that she delivered before the scheduled examination.
Among all women, two delivered preterm, woman B and woman E Table 1. Woman B delivered at 30 weeks of gestation, 3 weeks after betamethasone administration. Betamethasone concentration 48 hours after the first dose was 0. The neonate developed respiratory distress syndrome. Woman E delivered at 29 weeks of gestation, less than a week after betamethasone administration. Betamethasone concentration 48 hours after the first dose was 1.
The neonate did not develop respiratory distress syndrome. The other 3 women delivered at term. None of the neonates developed intraventricular hemorrhage or necrotizing enterocolitis. As shown in Fig. Among the measurements performed for each woman, the concentration was highest 36 hours after the first dose of betamethasone.
The concentration diminished gradually to a level close to the baseline at the 5 th measurement performed 5 to 7 days after the first dose of betamethasone.
Although the trend of sequential measurements was similar for the five women, there were obvious variations at each time point Fig. Trends of the sequential betamethasone concentration measurements of the 5 women included in the study.
Calculated half-life of betamethasone differed according to the time elapsed from its administration Table 2. Mean half-life after 36 to 48 hours from administration The evaluation of betamethasone measurement kit performance demonstrated a high precision for spiked betamethasone in the human sera pool: average coefficient of variation of 3. Analytical sensitivity lower limit of detection was 0. In this study we were able to measure betamethasone concentrations in the serum of pregnant women with the use of corticosteroid ELISA kit.
Among the measurements performed for each woman, the concentration was highest at 36 hours after the first dose of betamethasone followed by a gradual decrease to a level close to the baseline at the 5 th measurement at 5 to 7 days. The trend of sequential measurements performed similarly between all women; however the concentration varied at each time point between the five women. The near to baseline concentration at 5 to 7 days is similar to the described perinatal clinical effect that is best achieved within 7 days after drug administration [ 9 ].
The National Institutes of Health and the American College of Obstetricians and Gynecologists recommend routine glucocorticoid administration to women at risk for preterm birth between 24 and 34 weeks gestation to accelerate fetal lung maturation and to decrease the incidence of other neonatal morbidity and mortality related to prematurity [ 712 ].
When betamethasone is administered, the recommended regimen is two doses, 12 mg each, given intramuscularly 24 hours apart [ 712 ]. Although betamethasone treatment reduces mortality and morbidity in general, its effect on a particular woman is usually unpredictable. The current dosage of betamethasone was determined by Liggins and Howie during the s, and since then a fixed dosage is administered to all pregnant women regardless of gestational age, maternal body mass index, and whether a singleton or multiple gestation is present [ 8 ].
Additionally, betamethasone rapidly crosses the placenta [ 13 ]. Its administration to the pregnant mother inevitably exposes the fetus to glucocorticoid concentrations that may be inappropriate for the current stage of fetal development [ 14 ]. High blood pressure [ 15 ], reduced head circumference at birth [ 16 ], and reduced brain weight in monkey fetuses [ 1718 ] are among the several adverse effects reported after glucocorticoid given to enhance fetal lung maturity.
In view of that, the optimum betamethasone dosage and concentration in terms of benefit and safety to the developing fetus at any gestational age has not been established. Loehle et al. Their data showed that half the normal clinical dose, adjusted for weight, may be functionally adequate [ 14 ]. On the other hand, Ballabh et al. They reported that the reasons are due to shorter half-life and greater clearance of betamethasone in twin pregnancy than in singleton pregnancy.
This may be attributed to the presence of two fetoplacental units in twins, which causes greater metabolism of betamethasone than in singletons [ 19 ], or a dilution effect due to the increased maternal blood volume and total body water [ 20 ].
In contrast to the previous studies we show that there is a variation in the concentrations among women with singleton pregnancies and a fixed dosage, whether smaller or larger than the acceptable regimen, may not be sufficient to reduce perinatal complications among all women. The half-lives of betamethasone concentration found in the current study differ from the fixed 9.
This may be due to imprecision in the technique used to measure betamethasone concentrations. Ballabh et al. Additionally, and compared to their results, two different half-lives were noted in the current study. Sahin et al. This is due to the fact that the systemic concentration time profile for most drugs is best described by a multi-exponential function, thereby yielding more than one half-life to describe the drug.
The choice of a single appropriate half-life value for such drugs is unclear [ 21 ]. This may also be explained with the two-compartment model that adds a peripheral compartment to the one-compartment model. The peripheral compartment represents the opportunity for a drug to leave the plasma and enter other tissues. Among pregnant women, a third compartment may be present — the fetoplacental. Drugs transfer to the fetus across the placenta and elimination from the fetus is by diffusion back to the maternal compartment.
Moreover, the fetus plays an important role in the equilibrium of a compound because the fetus swallows amniotic fluid and urinates; there is a sort of drug recirculation within the fetal compartment along with the transfer back to maternal blood [ 22 ].
This may explain the existence of more than one half-life found in the current study. The results of the current study do not provide evidence as to the precise dosage of betamethasone that needs to be administered; the minimum betamethasone dosage that would be clinically effective is yet to be determined.
Basic pharmacologic principles suggest that the drug concentration in maternal serum may determine the fetal response and perinatal outcome and, as such, the optimal treatment regimen. Given that, the results of the current study may pave the way for future studies that could determine the optimum concentration and, accordingly, the dosage of betamethasone by investigating the minimum concentration that would be clinically effective to positively affect perinatal outcome.
Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med. Article Google Scholar. Preterm delivery.
Article PubMed Google Scholar. Hack M, Dandruff AA. Early Hum Dev.
Betamethasone phosphate disappeared rapidly from plasma (mean half-life = min) as betamethasone levels rose. Betamethasone plasma levels reached a peak. terminal half-life of 11 hours, about twice as long as the hours for oral and intramuscular dexamethasone. The mix- ture of betamethasone phosphate. The half-life of betamethasone was days. The elimination rate constant was h-1; the mean clearance was L/d. terminal half-life of 11 hours, about twice as long as the hours for oral and intramuscular dexamethasone. The mix- ture of betamethasone phosphate. The accepted half-life of betamethasone in the maternal circulation in humans is approximately 6 hours, and the half-life in the fetal circulation is. We aimed in the current study to assess the feasibility of a specific ELISA kit to measure the concentrations of betamethasone in maternal serum and to examine the trend of sequential measurements after a course of betamethasone for fetal lung maturity. The trend of sequential measurements performed similarly between all women; however the concentration varied at each time point between the five women. View author publications. The concentration diminished gradually to a level close to the baseline at the 5 th measurement performed 5 to 7 days after the first dose of betamethasone.We make sure that the fingertips you buy from our app or other are absolutely at the same cost as the therapy bus partner APSRTC. A - Your APSRTC bus fare can be canceled up to 2 hours before your departure.
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