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weight and multiple gestation on pharmacokinetics

Micaela Della Torre, MD, MS; Judith U. Hibbard, MD; Hyunyoung Jeong, PharmD, PhD; James H. Fischer, PharmD

OBJECTIVE: The goals of the study were to estimate the pharmacokinetic observed with maternal lean body weight (LBW). The relationship be-

parameters of standard dose betamethasone in a large obstetrics popula- tween the pharmacokinetic parameters and LBW remained linear over a

tion and evaluate the effect of maternal body size and multiple gestation on wide range of maternal body sizes. Multiple gestations did not affect the

the pharmacokinetic parameters and their observed variability. pharmacokinetic parameters.

STUDY DESIGN: This was a prospective pharmacokinetic study. Liquid

CONCLUSION: Individualization of betamethasone dosing by maternal

chromatography mass spectrometry was used to measure betametha-

LBW reduces variability in drug exposure. Mutiple gestations do not re-

sone plasma concentrations. Pharmacokinetic parameters and signifi-

quire betamethasone dosing adjustment, because pharmacokinetics

cant clinical covariates were estimated with mixed effect modeling.

Bootstrap analysis confirmed validity of the model. are the same as singleton gestations.

RESULTS: Two hundred seventy-four blood samples from 77 patients Key words: antenatal steroid, betamethasone, pharmacokinetics,

were obtained. The greatest effect on pharmacokinetic variability was prematurity

Cite this article as: Della Torre M, Hibbard JU, Jeong H, Fischer JH. Betamethasone in pregnancy: influence of maternal body weight and multiple gestation on

pharmacokinetics. Am J Obstet Gynecol 2010;203:254.e1-12.

physiologic changes that may alter

the disposition of drugs and the preg-

broventricular hemorrhage, and im-

proves overall neonatal survival.4,5 In

multiple gestations, there may be a less

clearance, and (3) determine whether

multiple gestations affect these pharma-

cokinetic parameters.

nant woman’s response.1,2 To date phar- beneficial effect of antenatal corticoste-

macokinetics during pregnancy are roid in reducing respiratory distress syn- M ATERIALS AND M ETHODS

known only for a few drugs. drome and death.6 Ballabh et al7 re- Patients

Antenatal steroid therapy has been ported a more rapid elimination half-life A prospective population pharmacoki-

demonstrated to improve neonatal out- of betamethasone in twin, compared netic study was conducted from March,

comes in premature neonates.3 This with singleton, pregnancies and believe a 2008 to November, 2008 at the Univer-

treatment decreases the risk of respira- decrease in betamethasone exposure sity of Illinois at Chicago. All pregnant

tory distress syndrome, reduces cere- may explain the reduced effectiveness in women, between 24 and 34 weeks’ gesta-

twins. However, the lack of difference in tion, ⬎18 years old, and clinically eligi-

this medication’s clearance and volume ble for an inpatient antenatal corticoste-

From the Division of Maternal Fetal of distribution conflicts with this inter- roid treatment course were approached

Medicine, Department of Obstetric and pretation. Few data exist about whether for enrollment. Participating subjects

Gynecology (Drs Della Torre and Hibbard), betamethasone that is given to obese received the standard regimen of beta-

and the Department of Pharmacy Practice women has the same beneficial neonatal methasone (equal amounts of beta-

(Drs Jeong and Fischer), University of effects as in normal-weight women. Re- methasone sodium phosphate and beta-

Illinois at Chicago, Chicago, IL. cently, a retrospective investigation of methasone acetate at a dose of 12 mg

Presented orally at the 30th Annual Meeting of ⬎1000 pregnant women who were re- every 24 hours for a total of 2 injections

the Society for Maternal-Fetal Medicine,

ceiving antenatal steroid treatment and intramuscularly). A blood sample of 8

Chicago, IL, Feb. 1-6, 2010.

stratified by body mass index (BMI) mL was collected from participants

Received Feb. 27, 2010; revised May 4, 2010;

accepted June 14, 2010.

found no difference among groups in within each of the 5 sampling windows:

Reprints: Micaela Della Torre, MD, MS, 3000 N

composite neonatal morbidity and mor- 5-20 minutes, 1-3 hours, 5-8 hours, and

Halsted, Suite 209 A, Chicago, IL 60657. tality rates.8 Similar results were noted 22-24 hours after the first intramuscular

3micaela@gmail.com. by another investigator.9 dose and 2-6 hours after the second in-

Authorship and contribution to the article is Aims of this study were to (1) examine tramuscular dose. Sampling windows

limited to the 4 authors indicated. There was the pharmacokinetics of standard dose were constructed from the D-optimal

no outside funding or technical assistance with intramuscular betamethasone in women sample times that were determined with

the production of this article.

between 24 and 34 weeks of gestation, the ADAPT II software (Biomedical

0002-9378/$36.00

(2) determine whether body size indica- Simulations Resource, Los Angeles,

Published by Mosby, Inc.

doi: 10.1016/j.ajog.2010.06.029 tors influence the variability in beta- CA).10,11 Enrollment occurred 7 days a

methasone volume of distribution and week, 24 hours daily. Participation in the

www.AJOG.org SMFM Papers

study was limited to the inpatient popu- Covariate analysis ences in the pharmacokinetic parame-

lation to ensure compliance with blood Bayesian estimates of the pharmacoki- ters between women with singleton and

draws. Fewer than 5 patients refused to netic parameters for individual patients multifetal pregnancies, a simulation ap-

participate in the study; the main reason were obtained from the pharmacoki- proach was used. These simulations used

for refusal was discomfort with the re- netic model without covariates (base a modified form of the final population

search-related venous punctures. The model), then graphic methods were used model that involved the addition of a co-

study was approved by the University of to screen for potential relationships be- variate in the expression for the beta-

Illinois at Chicago Institutional Review tween covariates and pharmacokinetic methasone apparent clearance (CL/F).

Board, and written informed consent parameters, with the use of the software This covariate represented a propor-

was obtained before any study-related S-Plus (version 6.1; Insightful Corpora- tional increase (from 0-40% in incre-

interventions. tion, Seattle, WA). Variables that were ments of 5%) in the apparent clearance

Demographic and clinical characteris- evaluated were total body weight (TBW), in women with multifetal pregnancies.

tics were recorded for each participant lean body weight (LBW),16 body surface For each incremental increase, 200 rep-

along with betamethasone dosing and area (BSA),17 BMI,18 gestational age licate datasets were simulated and fit to

sampling times. Blood samples were col- (calculated by last menstrual period, if the modified model. The percentage of

lected in evacuated tubes and were cen- available and confirmed by first- or sec- the 200 replications at each incremental

trifuged; the plasma was separated. To ond-trimester ultrasound scans), race, increase that showed a significantly

minimize hydrolysis of the esters, the age, twin or multiple gestation, concur- higher apparent clearance in multifetal

plasma was transferred immediately to rent liver or kidney disease, and presence pregnancies represented the power of

tubes that contained 100 mmol/L so- of preeclampsia. The LBW was calcu- the study to detect such a difference.

dium arsenate and potassium fluoride lated as described by Janmahasatian et

al16: Simulation of betamethasone

and was stored at –20°C.12,13 Of note, plasma concentrations

common definitions used in pharmacol- 9270 ⫻ TBW(kg) The effect on betamethasone systemic

ogy language and utilized in this work LBW(kg) ⫽ exposure of different body size–adjusted

are summarized in Appendix I for read- 8780 ⫹ 244 ⫻ BMI(kg ⁄ m2)

dosing schemes was examined by simu-

ers’ convenience. (1)

lation. Using the final population model,

Covariates identified in this equation betamethasone plasma concentrations

Betamethasone assay were first added alone to the base model; from time 0-24 hours after the dose were

Betamethasone plasma concentrations those covariates that produced a signifi- simulated for 77 patients for each of the

were measured with a validated liquid cant decrease in OFV (P ⬍ .01) were en- following doses: 12 mg (standard), 12

chromatography–tandem mass spec- tered into the model by a stepwise for- mg per 45 kg LBW (LBW-adjusted

trometry assay, which had been adapted ward inclusion backward elimination dose), and 12 mg per 70 kg TBW (TBW-

from previously published proce- approach. Continuous covariates that adjusted dose). Covariate values from

dures.12,14 Quality control data for the were identified were normalized to an the pharmacokinetic dataset were repro-

assay is described in Appendix II. accepted population standard (70 kg for duced in the simulation dataset. At each

TBW, 45 kg for LBW, and 1.73 m2 for dose, 1000 replicates of the dataset were

Pharmacokinetic analysis BSA) or study median (30 weeks’ gesta- simulated. The area under betametha-

The pharmacokinetic methods are sum- tional age). Linear and power functions sone plasma concentrations time curve

marized below and described in greater for continuous covariates and an indica- from time 0 to infinity (AUC) was calcu-

detail in Appendix II. Population phar- tor function for categoric covariates were lated at each simulated plasma concen-

macokinetic analysis of betamethasone evaluated to relate the covariates with the tration profile. The findings were exam-

plasma concentrations was performed pharmacokinetic parameters. ined graphically by the construction of

by nonlinear mixed effect modeling with box-plots of the AUCs, categorized by

Validation of the model dosage regimen and BMI (⬍25 kg/m2,

the use of the first-order conditional es-

The validity of the final population phar- 25-30 kg/m2, 31- 40 kg/m2, ⬎40 kg/m2).

timation method of the NONMEM soft-

macokinetic model was evaluated by

ware (version VI; Icon Development

bootstrap analysis. Resampling with re-

Solutions, Ellicott City, MD).15 Several R ESULTS

placement from the original dataset was

alternative pharmacokinetic models Eighty-four pregnant women were en-

used to construct 1000 bootstrap data-

were evaluated to describe the disposi- rolled in the study. However, 7 patients

sets. Each dataset was fit to the final pop-

tion of intramuscular betamethasone. had no evaluable betamethasone plasma

ulation model.

Model selection was guided by visual in- concentrations and were not included in

spection of diagnostic plots, standard er- Power analysis the population analysis. Isolated plasma

ror of the parameter estimates, and min- To determine the power of the design samples from other patients were ex-

imum value of the objective function that was implemented in this study for cluded from the dataset for the following

(OFV). the identification of important differ- reasons: 13 samples were outside the

SMFM Papers www.AJOG.org

TABLE 1 tive standard errors. The models in-

Demographic characteristics of subjects cluded estimates for the interindividual

Characteristic Measurement variability for CL/F, Q/F, Vss/F, and ab-

Patients, n 77 sorption rate constant along with a co-

..............................................................................................................................................................................................................................................

Blood samples, n 274 variance term between CL/F and Vss/F.

..............................................................................................................................................................................................................................................

a

The covariate analysis identified LBW

Age, y 27 (16–45)

.............................................................................................................................................................................................................................................. for CL/F and gestational age and LBW

a

Gestational age, wk 30 (21–34) for Vss/F as factors that significantly ex-

..............................................................................................................................................................................................................................................

Total body weight, kg a

85 (36–159) plained their variability. The influence of

..............................................................................................................................................................................................................................................

Lean body weight, kg a

48 (26–68) LBW on the interindividual variability of

..............................................................................................................................................................................................................................................

2a

CL/F was small, with variability reduced

Body mass index, kg/m 30 (16–53)

.............................................................................................................................................................................................................................................. by 10.4%. On the other hand, LBW and

Distribution, % gestational age explained nearly 40% of

.....................................................................................................................................................................................................................................

⬍25 kg/m 2

18 the interindividual variability on Vss/F.

.....................................................................................................................................................................................................................................

25-30 kg/m 2

32 No factors that significantly influenced

.....................................................................................................................................................................................................................................

2

interindividual variability in Q/F or ab-

31-39 kg/m 36

..................................................................................................................................................................................................................................... sorption rate constant were identified.

ⱖ40 kg/m 2

13 The final covariate models are provided

..............................................................................................................................................................................................................................................

Race/ethnicity, n in Appendix III.

.....................................................................................................................................................................................................................................

Black 64 Other descriptors of body size (TBW,

.....................................................................................................................................................................................................................................

BSA, and BMI), when individually input

Hispanic 22

..................................................................................................................................................................................................................................... into the covariate models for CL/F and

White 14 Vss/F, produced significant decreases in

..............................................................................................................................................................................................................................................

Fetuses, n the OFV. However, the decrease in OFV

.....................................................................................................................................................................................................................................

Singleton 64 was less than with LBW, and their addi-

.....................................................................................................................................................................................................................................

tion to covariate models that contained

Multiple 13

.............................................................................................................................................................................................................................................. LBW during the forward stepwise pro-

Preterm premature rupture of membranes/preterm labor/cervical 65 cess produced no further improvement

insufficiency, % in the model fitting. They therefore were

..............................................................................................................................................................................................................................................

Preeclampsia, % 28 not retained in the final covariate mod-

..............................................................................................................................................................................................................................................

Nonreassuring fetal well-being, % ⬍1 els. Interestingly, in contrast to the linear

..............................................................................................................................................................................................................................................

Other, % 6

relationship between LBW and CL/F or

..............................................................................................................................................................................................................................................

a

Vss/F, a power function better described

Data are given as median (range).

the relationship of TBW with CL/F or

Della Torre. Betamethasone in pregnancy. Am J Obstet Gynecol 2010.

Vss/F. The differences in the form of the

relationships with TBW, compared with

quantifiable limit of the assay; 3 samples tion because of an error in the determi- LBW, are apparent in Figure 1. As can be

had incomplete labeling, and 2 samples nation of her gestational age at time of seen in Figure 1, the individual Bayesian

were frozen before the red cells and admission. estimates of CL/F and Vss/F that were

plasma were separated. Thus, the final A 2-compartment model with first or- normalized by LBW remained constant

pharmacokinetic dataset consisted of 77 der of absorption and no lag time fit the over the range of observed body sizes,

pregnant women who contributed 274 betamethasone plasma concentration represented by BMI. On the other hand,

plasma samples for analysis. Of the 274 profile well. The pharmacokinetic pa- TBW normalized CL/F and Vss decrease

plasma samples, 233 samples (3.5 sam- rameters that were estimated included with increasing BMI. The final popula-

ples per patient) were from a singleton absorption rate constant, apparent dis- tion pharmacokinetic model was vali-

pregnancy, and 51 samples (3.9 per pa- tribution clearance (Q/F), CL/F, appar- dated from 1000 bootstrap replicates.

tient) were from multifetal pregnancies. ent volume of distribution of the central The bootstrapped medians for the fixed

The demographic and clinical character- compartment, and volume of distribu- and random effect parameters are pro-

istics of subjects are summarized in Ta- tion at steady state (Vss/F). Data that vided in Table 2. The mean estimates for

ble 1. Sixty-four women were carrying supported the structural and covariate the parameters from the final model

singleton pregnancies; 12 women were model selection are provided in Appen- were within 15% of the bootstrapped

carrying twin pregnancies, and 1 woman dix III. Table 2 lists the pharmacokinetic medians, which supported the stability

was carrying a set of triplets. Gestational parameters, covariate coefficients, inter- of the population model and accuracy of

age ranged from 21-34 weeks. One pa- individual variability and residual vari- the parameter estimates. Additionally,

tient received steroids at 21 weeks’ gesta- ability for the base, and final population the small relative standard errors and

www.AJOG.org SMFM Papers

TABLE 2

Population pharmacokinetic parameter estimates of betamethasone from the

base model (no covariates), final (covariate) model, and bootstrap analysis

Relative standard error

Base mode Final model Bootstrap median

Parameter estimate, n (%) estimate, n (%) (2.5th-97.5th percentile)

Fixed effects

.......................................................................................................................................................................................................................................................................................................................................................................

–1

Typical value of the absorption rate constant (h ) 3.1 (12.8) 3.0 (16.8) 2.8 (1.4-4.2)

.......................................................................................................................................................................................................................................................................................................................................................................

Typical value of apparent distribution clearance (L/h) 2700 (65.2) 2480 (63.7) 2425 (473-3960)

.......................................................................................................................................................................................................................................................................................................................................................................

Typical value of apparent clearance (L/h) 17.6 (4.3) — —

.......................................................................................................................................................................................................................................................................................................................................................................

Typical value of apparent clearance in a 45 kg lean body — 17.2 (4.0) 17.2 (15.8-18.6)

weight pregnant woman: lean body weight of effect on

apparent clearance (L/h/45 kg)

.......................................................................................................................................................................................................................................................................................................................................................................

Typical value of apparent volume of distribution of the central 48.5 (17.4) 43.7 (21.6) 34.9 (1.2-59.3)

compartment (L)

.......................................................................................................................................................................................................................................................................................................................................................................

Typical value of apparent volume of distribution at steady- 205 (7.4) — —

state (L)

.......................................................................................................................................................................................................................................................................................................................................................................

Typical value of apparent volume of distribution at steady- — 166 (13.5) 167 (102-215)

state in a 45 kg lean body weight woman: lean body weight

of effect on apparent volume of distribution at steady-state

(L/45 kg)

.......................................................................................................................................................................................................................................................................................................................................................................

Covariate for effect of gestational age on typical value of — 121 (37.6) 114 (37-196)

apparent volume of distribution at steady-state (L/45 kg)

................................................................................................................................................................................................................................................................................................................................................................................

Interindividual variability

.......................................................................................................................................................................................................................................................................................................................................................................

-1

Typical value of the absorption rate constant (h ) 1.3 (49.3) 1.3 (55.3) 1.2 (0.3-2.2)

.......................................................................................................................................................................................................................................................................................................................................................................

Typical value of apparent distribution clearance: coefficient of 271 (43.0) 221 (42.9) 200 (110-330)

variation (%)

.......................................................................................................................................................................................................................................................................................................................................................................

Typical value of apparent clearance: coefficient of variation 35.1 (17.0) 31.8 (20.0) 30.9 (25.2-37.0)

(%)

.......................................................................................................................................................................................................................................................................................................................................................................

Typical value of apparent volume of distribution at steady- 27.0 (17.0) 19.1 (37.1) 16.8 (10.1-22.7)

state: coefficient of variation (%)

.......................................................................................................................................................................................................................................................................................................................................................................

Covariance apparent clearance, apparent volume of 26.0 (20.6) 19.3 (27.0) 22.1 (7.2-37.0)

distribution at steady-state: coefficient of variation (%)

.......................................................................................................................................................................................................................................................................................................................................................................

Residual variability: coefficient of variation (%) 17.5 (20.7) 17.6 (20.4) 18.1 (14.6-21.8)

................................................................................................................................................................................................................................................................................................................................................................................

Della Torre. Betamethasone in pregnancy. Am J Obstet Gynecol 2010.

narrow bootstrapped 95% confidence nificant difference (P ⬍ .01) in CL/F be- sone AUCs (Figure 3, A). This finding

intervals (Table 2) confirm the precision tween singleton and multifetal pregnan- reflects the similarity between median

of the population parameters. Multiples cies was 65% when CL/F was assigned a LBW and TBW in this study and typical

gestation was not identified by the pop- value 25% higher in women with twin or values in women of this age. Variability

ulation analysis as significantly influenc- triplet pregnancies, 78% when CL/F was in betamethasone AUC is less with the

ing the pharmacokinetics of betametha- 30% higher in women with multifetal LBW-adjusted dose. The reason for the

sone in pregnant women. Box plots of pregnancies, and 86% when CL/F was differing variability among dose groups

the individual CL/F, Vss/F, and elimina- 35% higher in women with multifetal is illustrated by the box plots in Figure 3,

tion half-life grouped by number of off- pregnancies. B and D. For the LBW-adjusted dose,

spring (single vs twin or triplet) are Figure 3 summarizes the betametha- median betamethasone AUC is equiva-

shown in Figure 2. No statistically signif- sone AUCs from the simulated datasets. lent among the 4 BMI groups (Figure 3,

icant differences (P ⬎ .1, Student t test) The 12 mg (standard), 12 mg per 45 kg C). On the other hand, the median AUC

were observed for parameters between LBW (LBW-adjusted), and 12 mg per 70 for the other 2 dose groups varies with

single and multiple gestations. The kg TBW (TBW-adjusted) doses pro- BMI (Figure 3, B and D). For example,

power for detection of a statistically sig- duced comparable median betametha- because BMI increases from ⬍25 to ⬎ 40

SMFM Papers www.AJOG.org

FIGURE 1

tration of the standard dose decreases by

Graphic evaluation of relationship between body size and apparent

approximately 35% (Figure 3, B) and,

with administration of TBW-adjusted

clearance and volume of distribution at steady-state

dose, increases by approximately 30%

normalized by low or total body weight

(Figure 3, D). A

50

C OMMENT

A 2-compartment model best described 40

the disposition of betamethasone after

intramuscular administration in preg-

nant women at 21-34 weeks’ gestation. 30

The CL/F and Vss/F for the typical

woman in the study of 30 weeks’ gesta-

tion and 48 kg LBW were 18.4 L/hr and 20

202 L, respectively. These values are

comparable with estimates that derived

from the study reported by Peterson et 10

al19 after intramuscular administration

of the same formulation to pregnant

women. Conversely, the betamethasone

0

CL/F and distribution volume found by 12 22 32 42 52

Ballabh et al7 in pregnant women after Body Mass Index (kg/m2)

an intramuscular injection of the same

formulation were lower. Potential fac- B

tors that could explain the discrepancy 360

Apparent Volume of Distribution at Steady-State (L)

and Peterson et al include their use of an

300

immunoassay vs a chemical assay by

Peterson et al and us for measuring beta-

methasone plasma concentrations, the 240

inability of their analysis to characterize

the absorption and distribution phases

of the betamethasone plasma concentra- 180

tion-time curves, and their failure to sta-

bilize the betamethasone esters in the

120

plasma samples before storage.7,19 Any

of these factors may contribute to an ar-

tifactual elevation of AUC and, as a re- 60

sult, may explain the lower CL/F and vol-

ume of distribution described by Ballabh

et al.7 0

The betamethasone CL/F and Vss/F in 12 20 28 36 44 52

2

our study are higher than observed in Body Mass Index (kg/m )

studies of nonpregnant women.13 Even A, Individual Bayesian estimates of apparent clearance normalized to 45 kg low body weight (closed

after adjusting for a bioavailability of ap- triangle) or to 70 kg total body weight (closed circle) vs body mass index. The solid line represents a

proximately 70% for the betamethasone less smoother fit to the 45 kg low body weight apparent clearance; the dashed line represents the fit

phosphate/acetate suspension in preg- of a less smoother to the 70 kg total body weight apparent clearance. B, Individual Bayesian estimates

nant women,19,20 our CL/F and Vss/F of apparent volume of distribution at steady-state normalized to 45 kg low body weight (closed

remain approximately 1.2- to 1.6-fold triangle) or to 70 kg total body weight (closed circle) vs body mass index. The solid line represents a

higher than values reported in nonpreg- less smoother fit to the 45 kg low body weight volume of apparent distribution at steady-state; the

nant women.13,19,20 Betamethasone is a dashed line represents a less smoother fit to the 70 kg total body weight apparent volume of

low extraction ratio drug that was almost distribution at steady-state.

entirely eliminated by hepatic metabo- Della Torre. Betamethasone in pregnancy. Am J Obstet Gynecol 2010.

lism.13 Factors that explain a higher CL/F

www.AJOG.org SMFM Papers

FIGURE 2

of absorption, a reduction in plasma

Effect of single and multiple gestation on Bayesian estimates of protein binding, or enhanced hepatic

betamethasone pharmacokinetic parameters for individual patients metabolism. Observations of the same

A 50 relative difference as we observed in

CL/F and Vss/F between pregnant and

nonpregnant women after intravenous

40

administration argues against a change

Apparent Clearance (L/h/45 kg)

30 ation in plasma protein binding is also an

unlikely explanation because the frac-

20 tion of betamethasone that is bound to

plasma proteins is equivalent in preg-

nant and nonpregnant women.13,19-21

10

Consequently, enhanced hepatic metab-

olism represents the most probable ex-

0 planation for a pregnancy-related in-

Single Twin or Triplet crease in CL/F. Although pathways that

Offspring for Current Pregnancy mediate the hepatic metabolism of beta-

B 360 methasone are not established, studies

with other corticosteroids suggest a pri-

300 mary role for the cytochrome P450

Apparent Volume of Distribution at Steady-State (L/45 kg LBW)

isoenzyme 3A4.22

240 Pregnancy-related increases in clear-

ances of other 3A4 substrates have been

180 observed.1,23An increase in tissue bind-

ing of betamethasone provides the most

120 apt explanation for the higher Vss/F in

pregnancy.19,20,24 Among the demo-

60

graphic and clinical variables that were

evaluated, the covariates that affected

betamethasone CL/F and Vss/F the most

0

Single

Twin or Triplet

were descriptors of body size, which in-

Offspring for Current Pregnancy cluded LBW, TBW, BSA, and BMI. Scal-

C 16

ing of CL/F and Vss/F by LBW produced

the greatest reduction in the OFV and

14

interindividual variability. After LBW

12 was incorporated into the population of

pharmacokinetic models for CL/F and

Elimination Half Life (h)

10

Vss/F, the addition of other body size

8 measures yielded no further improve-

6

ment in the model fitting. The form of

the relationship with betamethasone

4 CL/F or Vss/F also differed between

2

LBW and TBW and other body size in-

dicators. The CL/F and Vss/F increased

0

linearly with increasing LBW, but non-

Single Twin or Triplet

linearly with increasing TBW. Accord-

Offspring for Current Pregnancy ingly, betamethasone CL/F that was

A, Box plots of apparent betamethasone clearance for singleton and multifetal pregnancies. B, Box scaled to LBW remained constant and al-

plots of apparent volume of distribution at steady-state for singleton and multifetal pregnancies. C, lowed drug exposure to be satisfactorily

Box plots of betamethasone elimination half life for singleton and multifetal pregnancies. The limits of estimated over a wide range of body

the box represent the 25th to 75th percentile of the distribution; the solid line in the box is the median compositions. On the other hand, CL/F

value; the whiskers represent the 10th and 90th percentiles of the distribution. that was scaled to TBW varies with

Della Torre. Betamethasone in pregnancy. Am J Obstet Gynecol 2010. changing body size and, when directly

extrapolated from normal to obese indi-

SMFM Papers www.AJOG.org

FIGURE 3

subjects with large BMIs. Figure 3, B-D,

Effects of dosage regimen and body size on betamethasone exposure

illustrates how these relationships im-

pact the administration of betametha- A B 2000

2000

sone doses. Compared with the use of a

1750

standard (unadjusted) or TBW-adjusted 1750

AUC (ng-h/ml)

AUC (ng-h/ml)

proach for dosing betamethasone offers 1250 1250

250

Doubts about the clinical benefit of

0 0

adjusting betamethasone doses for LBW 12 mg per 45 kg LBW 12 mg 12 mg per 70 kg TBW < 25 25 - 30 >30 - 40 > 40

were raised by recent retrospective anal- Dose Body Mass Index (kg/m2)

between neonatal outcomes and mater- C D

2000

2000

nal body size after standard courses of 1750 1750

AUC (ng-h/ml)

AUC (ng-h/ml)

1250 1250

< 25 25 - 30 >30 - 40 > 40

of betamethasone. The standard beta- < 25 25 - 30 >30 - 40 > 40

methasone regimen for treatment of pre-

maturity derives from a 1995 National Area under the plasma concentration-time curve (AUCs) were determined by simulating 1000 repli-

Institutes of Health Consensus Panel,26 cates of the final population model for each of the following doses: standard 12 mg, 12 mg/45 kg low

with the dose, timing, and frequency se- body weight (LBW; LBW-adjusted dose), or 12 mg/70 kg total body weight (TBW; TBW-adjusted

lected from empiric rather than scientif- dose). A, Box plot of simulated betamethasone AUCs for each of the 3 doses. B, Box plot of simulated

ically derived evidence.27 Support for a betamethasone AUCs after a 12-mg dose (not adjusted) grouped by the patients’ body mass indices:

lower dose is provided by a recent com- ⬍25 kg/m2, 25-30 kg/m2, ⬎30-40 kg/m2, or ⬎40 kg/m2. C, Box plot of simulated betamethasone

parison of 4 different betamethasone AUCs after a 12-mg/45 kg LBW dose (adjusted by LBW) grouped by body mass index: ⬍25 kg/m2,

regimens for the induction of fetal lung 25-30 kg/m2, ⬎30-40 kg/m2, or ⬎40 kg/m2. D, Box plot of simulated betamethasone AUCs after a

maturation in sheep.28 Induction of fetal 12 mg/70 kg TBW dose (adjusted by TWB) grouped by body mass index: ⬍25 kg/m2, 25-30 kg/m2,

lung maturation was comparable among ⬎30-40 kg/m2, or ⬎40 kg/m2. The limits of the box represent the 25th to 75th percentile of the

the 4 treatments, including a single dose distribution; the solid line in the box is the median value; the whiskers represent the 10th and 90th

regimen of intramuscular betametha- percentiles of the distribution.

Della Torre. Betamethasone in pregnancy. Am J Obstet Gynecol 2010.

sone acetate. Notably, the single-dose

betamethasone acetate regimen pro-

duced no detectable betamethasone offer any clinical advantages is uncertain. studies generally have found TBW to be

plasma concentrations in 2 of 3 fetuses Once the range of effective betametha- the best body size descriptor for volume

and maternal betamethasone plasma sone doses and plasma concentrations of distribution of lipophilic drugs like

concentrations were approximately one- are identified, studies such as ours pro- betamethasone.29 We are uncertain of

tenth of those seen after the standard vide a framework for individualization the reason for this discrepancy, but the

regimen. The results of Jobe and Soll25 of doses. lack of pregnant subjects in the other

suggest the potential for unnecessary Studies that involve other drugs sub- studies may offer an explanation. Finally,

drug exposure during pregnancy with stantiate the superiority of LBW com- although we demonstrated that LBW

the current dosing regimen and empha- pared with TBW for describing the effect was the best body size indicator among

size the need to better understand the of size on drug clearance across a broad those evaluated in the current study,

pharmacodynamic properties of beta- range of body compositions.29-31 From a none of the body size indicators, includ-

methasone in the mother and fetus, par- biologic perspective, these findings sug- ing LBW, were developed specifically for

ticularly with respect to lung maturation gest that LBW more directly mirrors the pregnancy. Development and evaluation

and adverse effects on fetal growth. functional capacity of the liver than of pregnancy-specific measures of body

Whether individualized doses by LBW TBW. In contrast to our results, other composition are indicated.

www.AJOG.org SMFM Papers

Gestational age also significantly con- slim mothers and underdosing mothers Maternal-Fetal Medicine; San Diego, CA; Janu-

tributed to variability in Vss/F, with with larger body size. However, therapeu- ary 31, 2009.

10. D’Argenio D. Optimal sampling times for

Vss/F increasing as a power function of tic levels must be identified, and we must

pharmacokinetic experiments. J Pharmacoki-

gestational age. The time profile of this gain a better understanding of its fetal and net Biopharm 1981;9:739-56.

change and relatively minor impact on maternal pharmacodynamics. Because we 11. D’Argenio D, Schumitzky A. ADAPT II user’s

Vss/F, approximately 18% from 24-34 could not demonstrate any difference in guide: pharmacokinetic/pharmacodynamic sys-

weeks’ gestation, suggest pregnancy-in- maternal pharmacokinetics with multife- tems analysis software. Los Angeles, CA: Bio-

duced increases in extracellular fluid as a medical Simulations Resource; 1997.

tal pregnancies, further work should focus

possible factor.1 on alternative reasons for that betametha-

12. Samtani MN, Lohle M, Grant A, Nathanielsz

PW, Jusko WJ. Betamethasone pharmacoki-

Higher order of pregnancy was not sone does not provide the same beneficial netics after two prodrug formulations in sheep:

found to alter the maternal pharmacoki- effects in babies who are born of multiples implications for antenatal corticosteroid use.

netics of betamethasone. The study had gestation, compared with their singleton Drug Metab Dispos 2005;33:1124-30.

sufficient power to detect at least a 30% counterparts. f 13. Petersen MC, Nation RL, Mc Bride WG,

difference in CL/F. The only other study Ashley JJ, Moore RG. Pharmacokinetics of be-

to compare pharmacokinetics in single- tamethasone in healthy adults after intravenous

ton and twin pregnancies found a sig- ACKNOWLEDGMENTS administration. Eur J Clin Pharmacol 1983;25:

643-50.

nificantly faster elimination half-life in We thank all the individuals who contributed to

14. Luo Y, Uboh CE, Soma LR, Guan F, Rudy JA,

women with twin pregnancies.7 Compa- the data collection without whom the project

Tsang DS. Resolution, quantification and confir-

rable with our findings, neither clearance could not have been completed: Maria Colon,

mation of betamethasone and dexamethasone in

MD; Cecilia Gambala, MD; Dennie Rogers, MD,

nor volume of distribution significantly equine plasma by liquid chromatography/tandem

and all the Obstetrics and Gynecology residents

differed for the 2 groups. The more rapid and Labor and Delivery/Mother Baby staff. mass spectrometry. Rapid Commun Mass Spec-

elimination was interpreted by the inves- trom 2005;19:825-32.

tigators as having the potential to lower 15. Beal SL, Sheiner LB. NONMEM users

REFERENCES guide, 2006. Ellicott City, MD: Icon Develop-

betamethasone plasma concentrations

ment Solutions;1989-2006.

and thus to explain the poorer response 1. Anderson GD. Pregnancy-induced changes in

16. Janmhasatian S, Duffull SB, Ash S, Ward LC,

to antenatal betamethasone in twin pharmacokinetics: a mechanistic-based ap-

Byrne NM, Green B. Quantification of lean body-

proach. Clin Pharmacokinet 2005;44:989-1008.

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2. Hodge LS, Tracy TS. Alterations in drug dis-

that clearance and volume of distribu- position during pregnancy: implications for drug

17. DuBois D, DuBois EF. Clinical calorimetry: a

tion, not elimination half-life, are the therapy. Expert Opin Drug Metab Toxicol formula to estimate the approximate surface

primary determinants of the plasma 2007;3:557-71. area if height and weight be known. Arch Intern

Med 1916;17:863-71.

concentration-time profile. Future in- 3. Antenatal corticosteroids revisited: repeated

courses. NIH Consens Statement Online 2000 18. Keys A, Fidanza F, Karvonen M, Kimura N,

vestigations should focus on alternative Taylor H. Indices of relative weight and obesity.

August 17-18;17:1-10.

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4. The effect of corticosteroids for fetal lung ma-

tamethasone in twin pregnancies and turity on perinatal outcomes. NIH Consensus 19. Petersen MC, Ashley JJ, McBride WG, Na-

should include reduced fetal bioavail- Statement Online 1994 February 28-March tion RL. Disposition of betamethasone in partu-

ability because of enhanced activity of 2;12:1-24. rient women after intramuscular administration.

placental drug metabolizing enzymes, 5. Roberts D, Dalziel SR. Antenatal corticoste- Br J Clin Pharmacol 1984;18:383-92.

roids for accelerating fetal lung maturation for 20. Petersen MC, Collier CB, Ashley JJ,

efflux transporter, or altered pharmaco-

women at risk of preterm labor. Cochrane Da- McBride WG, Nation RL. Disposition of beta-

logic responsiveness to betamethasone methasone in parturient women after intrave-

tabase Syst Rev 2006;3:1492-9.

in fetuses of twin or triplet pregnancies.2 nous administration. Eur J Clin Pharmacol

6. Burkett G, Baver CR, Morrison JC, Curet L.

Also, more pharmacodynamic studies of Effect of prenatal dexamethasone administra- 1983;25:803-10.

betamethasone that is given antenatally tion on prevention of respiratory distress syn- 21. Rasmussen BB, Larsen LS, Senderovitz T.

should focus on the identification of ef- drome in twin pregnancies. J Perinatol Pharmacokinetic interaction studies of atosiban

fective betamethasone maternal doses 1986;6:304-8. with labetalol or betamethasone in healthy fe-

7. Ballabh P, Lo ES, Kumari J, et al. Pharmacoki- male volunteers. BJOG 2005;112:14929.

and relative therapeutic plasma concen-

netics of betamethasone in twin and single- 22. McCrea JB, Majumdar AK, Goldberg MR,

trations in mothers and fetuses before et al. Effects of the neurokinin1 receptor antag-

ton pregnancy. Clin Pharmacol Ther 2002;71:

individualization of dosing by LBW can 39-45. onist aprepitant on the pharmacokinetics of

be used clinically. 8. Della Torre M, Hibbard J. Antenatal steroids dexamethasone and methylprednisolone. Clin

In summary, we estimated pharmacoki- for prematurity and maternal obesity: does obe- Pharmacol Ther 2003;74:17-24.

netic parameters for betamethasone for sity decrease the beneficial effects? Poster pre- 23. Tracy TS, Venkataramanan R, Glover DD, et al.

women between 21 and 34 weeks’ gesta- sented at: 29th Annual Meeting of the Society of Temporal changes in drug metabolism (CYP1A2,

Maternal-Fetal Medicine; San Diego, CA; Janu- CYP2D6 and CYP3A activity) during pregnancy.

tion at standard dosages. We demon-

ary 31, 2009. Am J Obstet Gynecol 2005;192:633-9.

strated that, across a wide range of mater- 9. Hashima J. The effect of maternal obesity on 24. Gibaldi M, McNamara PJ. Apparent vol-

nal body size, individualization of neonatal outcome in women receiving a single umes of distribution and drug binding to plasma

betamethasone dosage by LBW may be course of antenatal corticosteroids. Poster pre- proteins and tissues. Eur J Clin Pharmacol

preferable to limit the risk of overdosing sented at: 29th Annual Meeting of the Society of 1978;13:373-8.

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25. Jobe AH, Soll RF. Choice and dose of cor- celerating fetal lung maturation for women at the obese? Br J Clin Pharmacol 2004;58:

ticosteroid for antenatal treatments. Am J Ob- risk of preterm birth. Cochrane Database Syst 119-33.

stet Gynecol 2004;190:878-81. Rev 2008;4:CD006764. 30. Han PY, Duffull SB, Kirkpatrick CMJ, Green

26. Anonymous. Effect of corticosteroids for fe- 28. Jobe AH, Nitsos I, Pillow J, Polglase GR, B. Dosing in obesity: a simple solution to a big

tal maturation on perinatal outcomes: NIH Con- Kallapur SG, Newnham JP. Betamethasone problem. Clinl Pharmacolo Ther 2007;82:505-8.

sensus Development panel on the effect of cor- dose and formulation for induced lung matura- 31. Anderson BJ, Holford NHG. Mechanism-

ticosteroids for fetal maturation on perinatal tion in fetal sheep. Am J Obstet Gynecol based concepts of size and maturity in pharma-

outcomes. JAMA 1995;273:413-8. 2009;201:611.e1-7. cokinetics. Annu Rev Pharmacol Toxicol 2008;

27. Brownfoot FC, Crowther CA, Middleton P. 29. Green B, Duffull SB. What is the best size 48:303-32.

Different corticosteroids and regimens for ac- descriptor to use for pharmacokinetic studies in

APPENDIX I

Common definitions

Term Definition

Pharmacokinetics Time course of drug absorption, distribution, metabolism, and excretion in the body

................................................................................................................................................................................................................................................................................................................................................................................

Clinical pharmacokinetics Application of pharmacokinetics principles to safe and effective therapeutic management of

drugs in an individual

................................................................................................................................................................................................................................................................................................................................................................................

Pharmacodynamics Relationship between drug concentration at the site of action and resultant effect; includes

time course and intensity of therapeutic and adverse effects

................................................................................................................................................................................................................................................................................................................................................................................

One-compartment model All body tissue and fluid are considered a unit; based on the assumption that, after 1 dose of a

drug is administered, it distributes instantaneously to all body areas

................................................................................................................................................................................................................................................................................................................................................................................

Two-compartment model At least 2 different units: a central compartment, with rapid drug distribution, usually the

bloodstream and highly perfuse organs and a peripheral compartment, with slow distribution;

model implies the drug moves back and forth between the 2 compartments to remain in

equilibrium

................................................................................................................................................................................................................................................................................................................................................................................

First-order elimination Amount of drug that is eliminated over a period of time is directly proportional to the amount

of drug in the body; the total amount of drug eliminated over a set time period changes, but

the fraction of the drug that is eliminated over the given time remains constant

................................................................................................................................................................................................................................................................................................................................................................................

Bioavailability Fraction of a given drug dose that reaches the systemic circulation

................................................................................................................................................................................................................................................................................................................................................................................

Body size indicators Total body weight (kilograms)

.................................................................................................................................................................................................................................................

Body surface area (square meters): calculated surface of a human body (for many clinical

purposes body surface area is a better indicator of metabolic mass than body weight because

it is less affected by abnormal adipose mass)

.................................................................................................................................................................................................................................................

Body mass index (kilograms/square meter): weight (kilograms)/height (square meters)

.................................................................................................................................................................................................................................................

Lean body weight (kilograms) includes the weight of muscles, bones, tendons, ligaments, and

water in the body; everything except fat tissue

................................................................................................................................................................................................................................................................................................................................................................................

Clearance Rate of drug removal from the plasma, expressed as volume of plasma per given unit of time

................................................................................................................................................................................................................................................................................................................................................................................

Volume of distribution Extent of drug distribution into body fluids and tissues minus volume required to account for

all of the drug in the body, if the concentration in all tissues is the same as plasma

concentration

................................................................................................................................................................................................................................................................................................................................................................................

Volume of distribution at Relates total amount of drug in the body to a particular plasma concentration under steady

steady state state conditions

................................................................................................................................................................................................................................................................................................................................................................................

Intercompartmental Rate of drug moving back and forth between the central compartment and the tissues and

clearance fluid of the peripheral compartment, to maintain a status of pseudoequilibrium

................................................................................................................................................................................................................................................................................................................................................................................

Area under the plasma Area formed under the curve when plasma concentration is plotted vs time; expressed also as

concentration vs time total drug exposure: clearance ⫽ dose/area under the plasma concentration

curve

................................................................................................................................................................................................................................................................................................................................................................................

Della Torre. Betamethasone in pregnancy. Am J Obstet Gynecol 2010.

www.AJOG.org SMFM Papers

A PPENDIX II estimates of the fixed effect pharmacoki- variance-covariance matrix (ie, covari-

Betamethasone assay netic parameters. Models were tested ance between random effects set to 0)

Betamethasone plasma concentrations with and without an absorption lag time. was used for modeling the residual

were measured with validated liquid The first-order conditional estimation variability.

chromatography-tandem mass spec- method was selected for fitting the phar- After the base model was determined,

trometry assay that was adapted from macokinetic data. the next step in the modeling process

previously published procedures.12,13 A log normal distribution was as- involved identification of clinically mean-

The lower limit of quantitation was 1.05 sumed for the pharmacokinetic parame- ingful covariates for explaining the interin-

ng/mL. Samples with concentrations ters; variability among individuals (ie, dividual variability in the pharmacokinetic

above the upper limit of quantita- interindividual variability) for the phar- parameters. Bayesian estimates of the

tion,105 ng/mL, were analyzed after be- macokinetic parameters was described pharmacokinetic parameters for individ-

ing diluted 1:4 with blank plasma. The with the use of exponential random ef- ual patients were obtained from the base

between-run precision, based on the rel- fects. This relationship is illustrated for

model. Graphic and generalized additive

ative standard deviation of replicate clearance (CL) by the following equa-

modeling methods (S-Plus, version 6.1;

quality control (n ⫽ 7) was 1.3% at 402 tion:

Insightful Corporation, Seattle, WA) were

ng/mL, 4.7% at 80.5 ng/mL, 4.2% at 40.2

CL/Fi ⫽ TVCL ⫻ ei (1) used to screen for relationships between

n/mL, 5.5% at 4.02 ng/mL, and 2.9% at

covariates and pharmacokinetic parame-

1.05 ng/mL. The assay was specific for where CL/Fi is the estimated CL for indi- ters. The covariates that were evaluated

betamethasone, with resolution of beta- vidual i, typical value of clearance were total body weight (TBW), lean body

methasone base from the acetate and (TVCL) is the typical population value weight,15body surface area,16 body mass

phosphate esters. for CL, and i is the random effect that index,17 gestational age (calculated by last

represents the deviation of CLi from

menstrual period, if available, and con-

CLTV. The s are assumed to be distrib-

Explanation of equations utilized firmed by first or second trimester ultra-

uted normally with a mean of zero and

for pharmacokinetic modeling sound scan), race, age, multifetal (twin or

variance 2. The 2 is an estimate of the

Betamethasone plasma concentrations triplet) gestation, concurrent liver or kid-

interindividual variance for the pharma-

were analyzed with NONMEM software cokinetic parameter. ney disease, and presence of preeclampsia.

(version VI, level 1.0; Globomax LLC, An additive model (equation 2) was Covariates that were identified in the

Hanover, MD). Model building first fo- evaluated when problems occurred with screening analysis were first added alone to

cused on identification of an appropriate the exponential model: expressions for the pharmacokinetic pa-

structural (base) model, that consisted rameters in the base model with the use of

of a pharmacokinetic compartmental CL ⁄ Fi ⫽ TVCL ⫹ i (2) NONMEM. Covariates that produced a

model and expressions for describing the decrease in OFV ⬎3.84 (P ⬍ .05; degrees of

A full variance-covariance matrix (ie,

inter- and intraindividual (residual) freedom ⫽ 1) in the univariate analysis

inclusion of the off-diagonal elements

variabilities. The best model was selected were entered in a stepwise fashion into an

that represent the covariance between

based on (1) goodness of fit plots (such intermediate multivariate model and re-

random effects and indicate their degree

as those that were observed vs the model- tained if their addition decreased the OFV

of correlation) was implemented for

predicted population betamethasone by ⬎3.84. A backward elimination step

modeling the interindividual random ef-

plasma concentrations and weighted re- followed; the covariates that were entered

fects.

siduals vs predicted plasma concentra- into the model during the forward addi-

Residual (error) variability was de-

tions; (2) precision of the parameter es- tion step were eliminated individually and

scribed as a proportional error (equation

timates, as indicated by the relative retained in the final population pharmaco-

3):

standard error from the model fitting;

kinetic model if their removal increased

(3) minimum OFV (OFV; ie, the mini-

Yij ⫽ Ŷij ⫽ (1 ⫹ ij) (3) the OFV by ⬎6.6 (P ⬍ .01; degrees of free-

mization criteria in NONMEM), and (4)

dom ⫽ 1).

physiologic relevance of the parameter where Yij is the jth observed betametha-

Continuous covariates were normal-

estimates. The difference in the OFV be- sone plasma concentration in individ-

ized to an accepted population standard

tween competing models is approxi- ual i, Ŷij is the jth predicted betametha-

mately 2-distributed with the degrees of sone plasma concentration in (70 kg for TBW; 45 kg for lean body

freedom equal to the difference in the individual i, and ij denotes the ran- weight; 1.73 m2 for body surface area) or

number of parameters between the dom error between the measured and study median (30 weeks’ gestational

models. predicted jth observation in individual age); linear (equation 4) or power (equa-

One- and two-compartment models i. The s are assumed to be distributed tion 5) functions were used to assess

with first order absorption and elimina- normally with a mean of zero and vari- their influence:

tion were evaluated to describe the dis- ance of 2. The 2 is an estimate of the

position of betamethasone and provide intraindividual variance. A diagonal CLi ⫽ TVCL ⫹ (TBW ⁄ 70) ⫻ (4)

SMFM Papers www.AJOG.org

where represents the effect of the co-

variate on the TVCL.

A B

150 8

Categoric covariates were input as in- 140

120

CL ⁄ F ⫽ TVCL ⫹ I ⫻ 110 4

(6)

Weighted Residuals

100

2

where I is an indicator variable with a 90

80

value of 1, if the trait is present, and 0 70

0

otherwise. 60

-2

50

The simulations to determine the power 40 -4

of the design for the identification of im- 30

10

between women with single and multifetal 0 -8

(twin or triplet) gestations were performed 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 0 10 20 30 40 50 60 70 80 90 100

with a modified form of the final popula- Predicted Betamethasone Plasma Concentration (ng/ml)

C D

in the following equation: 150 8

Observed Betamethasone Plasma Concentration (ng/ml)

140

CL ⁄ Fi ⫽ CL ⁄ Ffinal model 130 6

120

⫻ twin pregnancy ⫻ e (7) 110

4

Weighted Residuals

100

2

where CL/Fi is the estimated CL/F for indi- 90

80

vidual i, CL/Ffinal model is the CL/F based on 70

0

covariate model, twin pregnancy is an addi- 50

40 -4

tional covariate for the simulation that 30

represents a proportional increase in CL/F 20 -6

10

in women with a twin or higher order 0 -8

pregnancy. twin pregnancy was varied from 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 0 20 40 60 80 100

0-40% in increments of 5%. The percent- Predicted Betamethasone Plasma Concentration (ng/ml)

age of the 200 replications at each incre- Goodness of fit plots for betamethasone plasma concentrations with the use of 1- and 2-compartment

mental increase that shows a significantly models with first-order absorption and elimination. A, Observed vs model-predicted betamethasone

higher CL/F in multifetal pregnancies rep- plasma concentrations from the 1-compartment model. B, Weighted residuals vs model-predicted

resented the power of the study to detect betamethasone plasma concentrations from the 1-compartment model. C, Observed vs model-

this difference. The increase in CL/F was predicted betamethasone plasma concentrations from the 2-compartment model. D, Weighted re-

considered significant if the decrease in the siduals vs model-predicted betamethasone plasma concentrations from the 2-compartment model.

OFV was ⬎6.6 and the lower 95% asymp- The solid line in A and C represents the line of identity. The solid line in B and D represents the

totic confidence limit for the coefficient zero-intercept line.

that represented the effect of multifetal Della Torre. Betamethasone in pregnancy. Am J Obstet Gynecol 2010.

⬎0.

For the simulations that were per- A PPENDIX III and volume of distribution at steady

formed to examine the effect of different Data that support the selection of the state (Vss/F). The less varied and more

body size–adjusted dosing schemes on structural pharmacokinetic model symmetric distribution of data around

betamethasone exposure, the area under A 2-compartment model with first-or- the line of identity in the Supplemental

the betamethasone plasma concentra- der absorption and no lag time fit the be- Figure, C compared with A and the zero

tion-time curve from time zero to infin- tamethasone plasma concentration pro- intercept line in D compared with B sup-

ity was calculated for each simulated file well (delta objective function, –183; port the suitability of the 2-compart-

plasma concentration profile by the P ⬍ .001; degrees of freedom ⫽ 2), com- ment model. The model included esti-

trapezoidal rule from time 0-24 hours af- pared with a 1-compartment model. mates for the interindividual variability

ter the dose was administered, with the Pharmacokinetic parameters of the (IIV) for CL/F, Vss/F, and absorption

area from 24 hours to infinity extrapo- model included absorption rate con- rate constant along with a covariance

lated by dividing the betamethasone stant, clearance (CL/F), apparent distri- term between CL/F and Vss/F. The IIV in

plasma concentration at 24 hours by the bution clearance, apparent volume of absorption rate constant was modeled

negative of the terminal slope. distribution of the central compartment, with an additive error, whereas an ex-

www.AJOG.org SMFM Papers

ponential model best described IIV for limits, which strongly suggested a lin- CL ⁄ F (L ⁄ hr) ⫽ TVCL45kg woman

the other parameters. The data did not ear relationship. After hypothesis test-

support allocation of IIV to apparent ing was completed, the effect of LBW (L ⁄ h ⁄ 45) ⫻ LBW ⁄ 45 kg

volume of distribution of the central on CL/F and Vss/F was simplified from

compartment. Residual variability was a linear expression to a direct propor- Vss ⁄ F (L) ⫽ (TVVss45kg woman

expressed with a proportional error tion for the final model. This transfor-

[L ⁄ 45 kg] ⫻ ⌰gestational age [wks]⁄40)

model. A linear relationship was se- mation provided a more clinically ap-

lected for the description of the rela- plicable expression and did not affect ⫻ LBW ⁄ 45 kg

tionship between low body weight either the fit or amount of variability

(LBW) and CL/F or Vss/F. The use of a explained by LBW. TVCL45kg woman and TVVss45kg woman

power equation did not improve the fit Covariate models for CL/F and Vss/F represent typical values of CL/F and

and yielded power coefficients that in- The final covariate models for CL/F Vss/F for a pregnant woman of 45 kg

cluded 1 within the 95% confidence and Vss/F were LBW. L represents clearance.

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