pharmacodynamic modeling during pregnancy

Approaches to Pharmacokinetic/ Pharmacodynamic Modeling During Pregnancy Elzbieta Wyska and William J. Jusko

The modern approach in the field of pharmacokinefics/pharmacodynamics is the development of models based on the mechanisms of drug action and their alteration of physiologic processes. Such models often require consideration of the input and disposition kinetics of the drug, distribution to sites of action (biophase), processes controlling receptor binding or mediator turnover, mechanisms of drug actha'ty, and signal transduction steps. Responses can often be categorized as: Direct (rapidly or slowly reversible), Indirect (inhibitory or sfimulatory), or Irreversible. Further, there may be alterations in the system owing to tolerance, counter-regulation, pathophysiology, or physiological changes such as gender or pregnancy. Mathematical and computational tools are necessary for processing data. This article overviews many available pharmacodynamic models with an indication of the diverse approaches for quantitation of pharmacologic responses. Examples from the literature are illustrated with emphasis on changes OCCUlTingin kinetics and dynamics during pregnancy. Copyright 9 2001 by W.B. Saunders Company main goals of pharmacokinetic/pharT hemacodynamic (PK/PD) modeling are: to conceptual!ze the system, to codify current facts, to test competing hypotheses, to identify controlling factors, to estimate inaccessible system variables, and to predict system response u n d e r new conditions. Appropriate PK/PD models can streamline the drug development process, help interpret why factors such as pregnancy cause altered drug effects, and help illuminate the knowledge base underlying basic and clinical pharmacology. Table 1 lists several major types of drug effects. Recognition of the mechanism of drug action and placement of the major process controlling drug effects into one of these categories is helpful in assigning the basic PK/PD model structure. A scheme representing main components of PK/PD models is depicted in Figure 1.1 As shown, there can be several steps between drug exposure in blood and the measured reFrom the Department of Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY. Supported by Grant 57980 from the National Institutes of Health (NIH). Address reprint requests to William J. Jusko, PhD, Department of Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY. Copyright 9 2001 by W.B. Saunders Company 0146-0005/01/2503-0003535. 00/0 doi:l O.1053/sper.2001.24905

124

sponse. The input and disposition processes involved in the pharmacokinetics are essential to provide the appropriate time-course of exposure to the drug. Drugs must reach their site of action and often it is feasible to use techniques such as microdialysis or positron emission tomography scanning to monitor the biophase. Alternatively, it may be possible to assume that penetration to the biophase is governed by Fick's Law of Diffusion, which can be captured with a rate constant, ke0. Turnover of mediators, or b o u n d receptors, represents Biosignal Flux. The Biosensor Process can be either the Hill function or other equation describing inhibition or stimulation of the production or dissipation processes if a mediator is involved. Alternatively, drugs can act as agonists or antagonists of receptor-mediated processes. Finally, there may be single or multiple, linear or nonlinear steps between the Biosignal and Response, which can be represented as Transduction processes. Sometimes a PK/PD model is selected on the basis of one of these components being rate-limiting in controlling the time-course of drug effects. During pregnancy, both the pharmacokinetics and pharmacodynamics of many drugs can be altered and higher doses of drugs may be required in comparison to n o n p r e g n a n t patients. This review shows, on the basis of examples taken from literature, the applicability and

Seminars in Perinatology, Vol 25, No 3 (June), 2001: pp 124-132

Pharmacokinetics/Pharmacodynamics in Pregnancy

Table l. Major Types of Drug Effects

A

possibilities of P K / P D modeling for evaluating and predicting drug responses during pregnancy that can contribute to the understanding of the underlying causes and optimizing the drug therapy in this patient population.

Simple, Reversible Direct Effects T h e concentration-effect relationship for many drugs may be described by a hyperbolic relationship called the Emax model or by its m o r e general form achieved by the addition o f o n e m o r e p a r a m e t e r (T), which influences the slope o f the curve. Such an equation known as the Hill function can be written as follows: E ~ , . Cg

(1)

+

where Cp is plasma drug concentration, Em~,, is the maximum effect attributable to the drug, ECs0 is the concentration yielding 50% o f Emax, and 3' is the Hill coefficient. T h e expected behavior o f the Hill function is shown in Figure 2. At high drug concentrations all curves will theoretically achieve an Em~x value o f 100%. All

0

i

|

|

20

4O

60

80

100

Concentration Figure 2. The sigmoid E=~ model and influence of T on the shape of the effect-concentration relationship. curves also have the same ECs0 shown as a concentration of about 18 in this graph. Values o f T> 1 produce steeper curves, while values o f T< 1 produce shallower curves. A drug with simple, reversible, direct effects and n o processes intervening such as biophase distribution or transduction can be portrayed as shown in Figure 2. An example o f drug with this type o f simple, direct response may be heparin, considered the drug o f choice for long-term andcoagulation during pregnancy. T h e results o f a PK/PD study p e r f o r m e d in 6 p r e g n a n t and 6 n o n p r e g n a n t women who were given heparin at a dose o f 143 U / k g subcutaneously revealed large differences in both pharmacokinetics (Fig 3A) and activated partial thromboplastin times - aPTI" (Fig 3B) between these study populations. 2 To interpret why responses were so markedly reduced during pregnancy, we plotted aPTF versus heparin con-

Drug Figure 1. Components of PK/PD models including pharmacokinetic factors controlling plasma concentrations (Cp), distribution rate constant to a biophase (keo) with effect site concentration (Ce), inhibition or stimulation (H) of the production (ki.) or removal (ko.o of a mediator biosignal, and transduction of the response (R).I

y=2

100'

Reversible Direct Rapid Slow Indirect Synthesis, secretion Cell trafficking Enzyme induction Irreversible Chemotherapy Enzyme inactivation

E =

125

4" k l n r

Disposition Biophase Biosensor Biosignal Kinetics Distribution Process Flux L PharmacokineUcsA I

Transduction

Pharmacodynamics

Response

Wyska and Jusko

126

0.25.

so

50.

0.20-

45

45.

o6 40

40.

0.15

~

i 0.10,

30

O.OS,

25

C

3s

~

30 25

E

a.

20

0.00 0

200 400 Time (mln.)

600

0

200 4~) 600 Time (min.)

centrations as shown in Figure 3C. The profiles do not superimpose indicating an intrinsic difference in clotting response during pregnancy. The baselines appear to differ appreciably, but the lower plasma heparin concentrations during pregnancy m a d e it impossible to assess whether Em~'br ECs0 or both factors were also affected. For such evaluation it is necessary to perform such studies with higher doses to achieve large plasma concentration ranges, so as to observe m a x i m u m - d r u g responses. An in vitro assessm e n t would also be helpful. When dosages are limited or the occurrence o f side effects prevents the administration o f high doses or the drug has a long elimination haft-life resulting in narrow concentration ranges being studied, linear (Eq. 2) and loglinear (Eq. 3) equations are often used for the description o f concentration-effect relationships, especially in h u m a n studies:

20 0.01 ..... O11 ....... "1 Heparln Conc. (unitslml)

Figure 3. Time-course of plasma heparin concentrations and activated partial thromboplasfin times (aP3T) after subcutaneous administration of 143 U/kg of hepafin to pregnant (solid circles) and nonpregnant (open circles) pafientsY

Levy opening up the field o f pharmacodynamics in the 1960s. T h e Levy "k" m concept": E = Em

k.m 9.3

t

(4)

indicates that the decline in drug effect with time from an initial effect (Era) should be linear with a slope of k.m/2.3. Such a behavior pattern is seen in the profiles in Fig 3B. T h e time course o f many simple direct pharmacodynamic responses, such as in the case o f neuromuscular blocking agents, yields information about kinetic and dynamic processes controlling drug effects without the n e e d for plasma concentration data. Such a model has b e e n developed by Levy for succinylcholine. 3 In this model, the duration o f drug effect (td) is controlled by dose and elimination rate constant (k) according to the equation:

1

E = E0 - S- C o

(2)

td = ~" (ln Dose -- In A~i.)

E = E1 ---+m - l o g Cp

(3)

where Amin is the m i n i m u m effective dose. Ano t h e r important parameter is the t d 9 R p r o d u c t which is:

where E 0 and E I are baseline effect values and S and m are the slopes o f suitable plots. These models predict no Ema~ and the loglinear model suggests a threshold concentration, below which n o effect occurs.

Time Course of Simple Direct Effects T h e first appreciation that pharmacokinetic factors such as the elimination rate constant (k) and pharmacologic factors such as "m" in Eq. 3 were of importance in controlling the timecourse of simple direct effects led to Gerhard

td" R = m ( l n Dose - In Ami.)

(5)

(6)

where m is from Eq. 3 and R is the k 9 m / 2 . 3 slope from Eq. 4. A pharmacodynamic study was p e r f o r m e d in a group o f 35 patients: term-pregnant patients u n d e r g o i n g caesarean section, postpartum patients u n d e r g o i n g tubal ligation, a n d nonpregn a n t women taking and not taking oral contraceptives who were given succinylcholine intravenously at a dose of 1 mg/kg. 4 Despite comparable 25% to 75% recovery times from

127

Pharmacokinetics/Pharmacodynamics in Pregnancy

Table 2. Muscle Relaxation Recovery Times and Cholinesterase Activity for Succinylcholine Given as 1 mg/kg to Various Women Group

No.

Time to 25 % Recovery td (rain)

25 %-75 % RecoveryTime (rain)

ta 9 R (%)

Cholinesterase Activity (U/mL)

Controls OC users Term-pregnant Postpartum

14 7 5 8

8.35 8.32 7.83 11.42

1.70 1.73 1.38 1.58

246 240 284 361

5.01 4.81 3.66 2.84

Data from ref 4. muscle relaxation in all groups o f patients, the values o f time to 25% recovery (td) and ta'R p r o d u c t were significantly higher in postpartum patients (Table 2). These data are consistent with a reduced value o f Amin occurring in the postpartum group. Receptor

Binding Model

T h e onset of action o f some drugs such as calcium channel blocking agents is delayed. They inhibit calcium transport through calcium channels in plasma membranes, which results in the relaxation o f the peripheral arterial vascular tone and reduction in blood pressure. T h e pharmacodynamic model proposed for these drugs as well as differential equations are presented in Figure 4. According to this model, the drugs interact with the ion-channels at the site o f action with second-order association constant

Compartment

+

(R)

Drug-Receptor ] Complex ~

(RC)

(kon) and the first-order dissociation rate constant (kou). Data for 10 mg doses o f nifedipine from 2 studies: n o n p r e g n a n t Japanese patients with hypertension 5 and postpartum patients with preeclampsia 6 were compared. Figure 5 presents plasma concentration versus time data fitted to a one-compartment model with first order absorption (A, 1%, ke) and blood pressure data fitted with the second equation in Figure 4 (kon, kotr, Emax). Pharmacokinetic and pharmacodyna-mic parameters are presented in Table 3. T h e patients with preeclampsia exhibited considerably lower serum concentrations (AUC = 39 n g ' h / mL) in comparison to n o n p r e g n a n t patients (AUC = 353 ng" h / m L ) probably because o f a greater first-pass loss and faster elimination o f the drug. Differences in dynamics such as in Emax and KD were obtained, but it is not possible to trust these values without studying wider ranges o f doses and concentrations. It would be worthwhile to repeat these studies with greater experimental rigor.

Biophase

Pharmacological

Effect(E)

d[RCl - : k , , -[Cp]-([RTI -- [RCI) - kon" [RC] dt dE - - = k o , 9[Cp]- ( E m , - E ) - kon .E dt

Figure 4. Receptor binding model and differential equations where 1% is a first-order absorption rate constant, 1%is a first-order elimination rate constant, kon is a second-order association rate constant, and ko~ is a first-order dissociation rate constant.

Distribution

For some drugs, having a distinct delay in the occurrence of peak effects relative to plasma concentrations, a hypothetical effect compartm e n t equivalent to a biophase can be proposed (Fig 6). 7 It is treated as an additional compartm e n t linked to the plasma c o m p a r t m e n t by a first-order process, and it is assumed that the a m o u n t o f drug in the biophase does not contribute to the pharmacokinefics of drug in plasma. Graphical representation of the delay observed is the presence o f hysteresis loop when plotting effect versus Cp. It is expected that a plot using the drug concentration in the real drug biophase (Ce) will eliminate this delay. T h e

128

Wyska and Jusko

9

0

B

A

Oo ~ "0-

I ~~. o 10 ~

0000 "

"0.

87

.~ 20

"0

"O, 9

.~m 10 (.1

9 0

|

0

|

2

4

~

9.

r

0.1 o

|

6

m

8

9

t~

0 0

|

|

2

4

0.1 o 6

T i m e (h)

rate of change of drug concentration in the effect c o m p a r t m e n t can be described by the first equa~on in Figure 6. T h e relationship between drug concentration in the effect c o m p a r t m e n t and the pharmacological effect (E) may be expressed by the Em~x or o t h e r models (Eq. 1-3). Pharmacodynamic data from a study perf o r m e d by Caritis et ala in a group o f 6 p r e g n a n t volunteers who were given intramuscularly 10 m g ritodrine, a /3-adrenergic receptor agonist used for the treatment o f preterm labor, may be fitted with this model. Pharrnacokinetic data were described by a two-compartment model with first-order absorption (Fig 7). T h e middle graph shows hysteresis when effect is plotted versus Cp but a linear relationship when plotted versus the calculated biophase concentration (Ce). Any time delays in drug effects will produce hysteresis and this model is only appropriate if diffusion to the site of action is the cause of such delay in onset of the effect.

Table 3. Pharmacokinetic and Pharmacodynamic Parameters Estimated After Administration of Nifedipine at a Dose of 10 mg to Nonpregnant and Postpartum Patients

A (ng/mL) ke (h -1) lq (h -1) ko, (mL/ng 9 h) kotr (h -1) Er,~, (mm Hg) KD = koer/ko.

1

" 9

10

Time (h)

Parameter

Figure 5. Pharmacokinetics of nifedipine (open circles) and changes in blood pressure (solid circles) after oral doses of 10 mg nifedipine administered to (A) nonpregnant and (B) postpartum patients. Symbols are data from Shimada et al5 and Barton et al6, and solid lines are fittings to the receptor binding model shown in Figure 4.

Nonpregnant 133.48 0.39 2.70 0.04 0.47 35.92 11.75

Postpartum 30.14 0.76 2.33 0.12 0.42 14.27 3.50

Indirect

Response

Models

A family o f 4 basic indirect response m o d e l s can be used (Fig 8) to describe the p h a r m a c o dynamics o f drugs with mechanisms p r o d u c ing indirect responses, d e p e n d i n g o n the influence o f the d r u g (stimulation o r inhibition) o n the p r o d u c t i o n (kin) or dissipation (kout) process normally controlling e n d o g e n o u s levels o f response. 9 An example of application of the stimulatory indirect response model III to calculate pharmacodynamic parameters is provided in Figure 9 and Table 4. Data were obtained from a study p e r f o r m e d in a group o f 24 p r e g n a n t patients and 8 controls who were administered thyrotropin-releasing h o r m o n e (TRH) as an intraveneous bolus at a dose o f 400 /zg to p r o m o t e surfactant synthesis in the fetal lung. 10 Pharmacodynamic response was measured by changes in

+

dC, =k,o(C p -(2,) -. keo x

+--

.

dt ,,

i

E m ~ 9C c

ECso + C ,

Figure 6. Schematic presentation of the PK/PD model based on biophase distribution where Ce is the concentration of drug in the effect compartment and ke0 is the first-order rate constant for drug equilibration with the effect site.

Pharmacokinetics/Pharmacodynamics in Pregnancy

25 '

Z5

25 9

9

(-) B

~"

10o'~ J

I=

5

X"

, 0

100

o

.,f S

0.t 200

C

5) 15.

e,,

0

129

0

300

. 0

.

10

. 20

. 30

. 40

50

Plasma Conc. (nglml)

Time (min.)

0 9

.

0

5

.

. 10

. lS

. 20

25

Biophase Conc. (ng/ml)

Figure 7. Plasma ritodrine concentration (open circles) and changes in heart rate (solid circles) (A) versus time, changes in heart rate (B) versus plasma ritodrine concentration, and changes in heart rate (C) versus predicted biophase concentration after intramuscular administration of 10 mg ritodrine to pregnant women. Experimental data are from Caritis et al.s Fittings to PK/PD model based on the biophase distribution model gave: Em~ = 38.29, ECs0 = 22.13 n g / m L and ke0 = 0.028 min -1. plasma thyroxine (TSH) a n d prolactin (PRL) concentrations. T h e o n e - c o m p a r t m e n t pharrnacokinetic m o d e l (C 0, 1%) was fitted to the T R H concentration curves with a m o d e r a t e difference in kinetics found. C o m p a r a b l e values o f SC~0 in b o t h patient populations in relation to T S H indicate that, in contrast to suggestions o f Bajoria et al, 1~ p r e g n a n c y does not seem to alter sensitivity to TRH. Observed decreased concentrations of T S H in p r e g n a n t w o m e n are probably caused by the lower T R H levels in p r e g n a n t

Model:

I

I. I N H I B I T I O N

Figure 8. Family of pharmacodynamic indirect response models and differential equations describing production (kin) and loss (kout) of factors controlling the response variable (R). The IC50 and SC50 are the drug concentrations producing 50% of maximum alterations Imax or 8max .9

d_R_R= k i n . ( 1 dt

patients. Also, these patients received a single dose of 12 m g d e x a m e t h a s o n e intramuscularly before entering the study a n d it is known that pharmacological doses o f glucocorticoids may inhibit TRH-stimulated T S H secretion. 11 T h e m a r k e d increase in PRL is interesting and similar SC50 values were f o u n d in the 2 groups indicative of similar sensitivity. T h e greater response o f PRL in p r e g n a n c y can be attributed to the higher baseline a n d ki, values. It was shown by Sun and Jusko 12 that higher baselines can

IH

IH. STIMULATION - !~.

- k,. Imffi-Cp - ) - ko~ ICso + Cp

- koet

dR - - = ki. - ko=" (1 dt

0
d R = ki ~ . (1 -t S . ~

d---t-

9 Cp

s-C-~+ C'p) - k o = .R

S=~0

0
H IV

I...Cp ).R IC5o- Cp

IV. STIMULATION - kout d R = ki ~ _ kou,. ( 1 4 - S . .-x - Cp -)" R dt 8C5o + Cp

Smx>0

Wyska and Jusko

130

100

25 t 9

c

20

10

, .

"/"X

~

~ 1 -20

15000

~.o

g

, 0 20 40 Tlme (mln.)

9 0 , 60

12500

"-

il 0

E

75oo

a.

5ooo

2500 , 20 40 Time (mln.)

0 60

result in larger responses for drugs with indirect mechanisms. Signal

Tr-nsduction

Model

Pharmacological effects of e n d o g e n o u s comp o u n d s ( h o r m o n e s ) a n d exogenous substances (therapeutic drugs) are often p r o d u c e d via signal transduction processes. These cascade responses are often initiated by the interactions between h o r m o n e or d r u g molecules a n d their specific m e m b r a n e receptors and very often seco n d messengers (such as cyclic AMP , calcium ion) are involved in the processes. These messengers play i m p o r t a n t roles in regulating the cascade steps in multiple processes leading to their pharmacological e n d points, la T h e signal transduction m o d e l links the phar-

Table 4. Pharmacokinetic and Pharmacodynamic Parameters Estimated After Administration of TRH at a Dose of 400/~g to Nonpregnant and Pregnant Patients

Parameter

Nonpregnant

Pregnant

Co (ng/mL) 1% (min -1) TSH ki.. (pJU/mL 9 min) kout (min -1) SC5o (ng/mL) Sm~, PRL k~.n (/~IU/1 9 min) 1%,t (min -1) SC50 (ng/mL) Sm~,

53.28 0.16

81.15 0.15

0.09 0.05 6.25 25.82

0.07 0.05 59 22.61

3.99 0.03 30.00 889

142.60 0.05 27.91 16.40

0

20 40 Time (min.)

60

Figure 9. Concentration versus time profiles for TRH, TSH, and PRL measured in a group of pregnant (solid circles) and nonpregnant (open circles) patients. Symbols are data from Bajoria et all0 and solid and dotted lines are fittings to model III in Figure 8.

macokinetic profile o f the tested c o m p o u n d , rec e p t o r occupancy, a n d cascade steps for the signal transduction process as shown in Figure 10. T h e signal is delayed by the m e a n transit time (~') before p r o d u c i n g an observed effect9 T h e p r o d u c t i o n and loss o f effect is d e p e n d e n t on first-order rate constants which are equivalent to the reciprocal o f the transit time. Labetalol, a nonselective/3- and post-synaptic a - a d r e n o c e p t o r blocking a g e n t is c o m m o n l y used in hypertension o f pregnancy. Figures 11A a n d B show application of signal transduction m o d e l to fit data o b t a i n e d by Saotome et all4 at steady-state after oral administration o f labetalol at a dose o f 450 m g to a p r e g n a n t w o m a n d u r i n g o n e dosage interval. For comparison, Figure 11C represents fitting to this m o d e l o f data f r o m a study p e r f o r m e d by M a r o n d e et al 1~ in a g r o u p of 11 n o n p r e g n a n t patients with m i l d to m o d e r ate hypertension. T h e latter patients were given a single dose of 200 m g labetalol. Plasma labetalol concentration-time data were described by

Response

Oq

Figure 10. Basic scheme and differential equation for the signal transduction model where E is the measured drug effect and * is the mean transit time.

Pharmacokinetics/Pharnu~odynamics in Pregnancy

~100o o

9

A

Figure 11. Pharmacokinetics of labetalol (open circles) and changes in BP (solid circles) in (A and B) 1 pregnant and (C) 11 nonpregnant patients. Symbols are experimental data from Saotome et all4 and Maronde et allS and solid lines are fittings to the signal transduction model in Figure 10.

|

is

m

~ O

E to

o

i

~ rn

0 60

, 80

, 100

Conclusions

T o p e r f o r m a c o m p l e t e a n d m e a n i n g f u l pharm a c o d y n a m i c data analysis, m e a s u r e m e n t s s h o u l d be sensitive, gradual, r e p r o d u c i b l e , objective, a n d relevant to efficacy. T h e y s h o u l d encompass major contributing intermediatory steps w h e n complexities intervene in c o n t r o l l i n g responses. Studies s h o u l d i n c l u d e the baseline ( p l a c e b o dose) a n d span 2 to 3 dose levels with effects f r o m 0 to Emax. I n addition, m o d e l s s h o u l d recognize the m e c h a n i s m ( s ) o f d r u g action. It has b e e n shown that diverse P K / P D m o d e l s

T a b l e 5. Pharmacokinetic and Pharmacodynamic

Parameters Estimated After Administration of Labetalol to Nonpregnant (200 mg, single dose) and Pregnant (450 mg, steady-state) Patients

A (ng/mL) B (ng/mL) 1% (h -a) Ot (h -1) /3 (h -a) ~- (h) ECso (ng/mL) Em~,

r-

100

i

m

Q

s

I= I

Nonpregnant

Pregnant

421.26 32.21 1.31 0.78 0.09 0.70 27.32 32.09

470.31 39.75 2.33 0.51 0.06 1.90 141.90 30.00

O

'15.

100~Q ~ O

10,

9

O

o

~ O.

III

E IO

5'

o

10

Time (h)

E

O,. 20' m

.o.

,-o

120

a t w o - c o m p a r t m e n t o p e n m o d e l with first-order absorption. T h e results are p r e s e n t e d in T a b l e 5. As can be seen f r o m this table, the ECs0 ~ l u e f o r the p r e g n a n t p a t i e n t was m u c h h i g h e r t h a n f o r the n o n p r e g n a n t patients. This suggests t h a t the p r e g n a n t patient was m u c h less sensitive to labetalol, a l t h o u g h she achieved a c o m p a r a b l e theoretical Em~x.

Parameter

O

~E

s

lOOO

g

"O

~g

C

30' "!" E 25.

B O

2O

131

95

100

t04

Time (h)

108

4

8

'D,

10

G.

Time (h)

relating to m e c h a n i s m s o f action a n d physiological processes exist in p h a r m a c o l o g y . T h e examples p r o v i d e d in this article, a l t h o u g h o f t e n inc o m p l e t e with insufficient doses, indicate that m a r k e d alterations in b o t h d r u g disposition (PK) as well as responses (PD) can o c c u r d u r i n g p r e g n a n c y . O p p o r t u n i t i e s to assess d r u g response d u r i n g p r e g n a n c y s h o u l d use o p t i m i z e d e x p e r i m e n t a l designs a n d insightful m o d e l s to recover m e a n i n g f u l P K / P D parameters.

References

1. Jusko WJ, Ko HC, Ebling WF: Convergence of direct and indirect pharmacodynamic response models. J Pharmacokinet Biopharm 23:5-8, 1995 2. Brancazio LR, Roperd KA, Stierer R, et al: Pharmacokinetics and pharmacodynamics of subcutaneous heparin during the early third trimester of pregnancy. Am J Obstet Gynecol 173:1240-1245, 1995 3. Levy G: Pharmacokinetics of succinylcholine in newborns. Anesthesiology 32: 551-552, 1970 4. Leighton BL, Cheek TG, GrossJB, et al: Succinylcholine pharmacodynamics in peripartum patients. Anesthesiology 64:202-205, 1986 5. Shimada S, Nakajima Y, Yamamoto K, et al: Comparative pharmacodynamics of eight calcium channel blocking agents in Japanese essential hypertensive patients. Biol Pharm Bull 19:430-437, 1996 6. Barton JR, Prevost RR, Wilson DA, et al: Nifedipine pharmacokinetics and pharmacodynamics during the immediate postpartum period in patients with preeclampsia. Am J Obstet Gynecol 165:951-954, 1991 7. Sheiner LB, Stanski DR, Vozeh S, et al: Simultaneous modeling of phalmacokinetics and pharmacodynamics: Application to d-tubocurarine. Clin Pharmacol Ther 25: 358-371, 1979 8. Caritis SN, Venkataramann R, Cotroneo M, et al: Pharmacokinetics and pharmacodynamics of ritodrine after intramuscular administration to pregnant women. Am J Obstet Gynecol 162:1215-1219, 1990 9. Dayneka NL, Garg V, Jusko WJ: Comparison of four

132

Wyska and Jusko

basic models of indirect pharmacodynamic responses. J Pharmacokin Biopharm 21:457-478, 1993 10. Bajoria R, Oteng-Ntim E, Peek MJ, et al: Pharmacokinetics and pharmacodynamics of TRH during pregnancy. Obstet Gynecol 90:176-182, 1997 I1. Farwell AP, Bravelman LE: Thyroid and antithyroid drugs, in Hardman JG, Limbird LE (eds): Goodman and Gilman's The Pharmacological Basis of Therapeutics (ed 9). New York, NY, McGraw Hill, 1996, pp 1383-1409 12. Sun Y-N, Jusko wJ: Role of baseline parameters in determining indirect pharmacodynamic responses. J Pharm Sci 88:987-990, 1999

13. Sun Y-N,Jusko WJ: Transit compartments venus gamma distribution function to model signal transduction processes in pharmacodynamics. J Pharm Sci 87:732-737, 1998 14. Saotome T, Minoura S, Terashi K, et al: Labetalol in hypertension during the third trimester of pregnancy: its antihypertensive effect and pharmacoldnetic-dynamic analysis. J Clin Pharmacol 33:979-988, 1993 15. Maronde RF, Robinson D, Vlachakis ND, et al: Study of single and multiple dose pharmacokinetic/pharmacodynamic modeling of the antihypertensive effect of labetalol. A m J Med 75:46-46, 1983