TAGEDENS E M I N A R S I N P E R I N A T O L O G Y 44 (2020) 151227

Available online at www.sciencedirect.com

Seminars in Perinatology
www.seminperinat.com

Pharmacokinetic studies in pregnancy

Michael J. Avram
Department of Anesthesiology, Northwestern University Feinberg School of Medicine, 330 E. Superior Street, Morton 4-660, Chicago, IL,
United States

A R T I C L E I N F O AB STR ACT

Keywords: The effects of the many biochemical and physiologic changes of pregnancy on the dose-
pregnancy response relationship of drugs administered to pregnant women are poorly understood.
pharmacokinetics The dose-response relationship is affected by pharmacokinetics, or what the body does to
pharmacodynamics a drug, and pharmacodynamics, or what a drug does to the body. Insights into the potential
dose-response effects of the changes of pregnancy on one aspect of the dose-response relationship of a
longitudinal studies drug can be obtained by studying the pharmacokinetics of the drug in the various stages of
pregnancy and the postpartum period. There are several available approaches to studying
pharmacokinetic changes in pregnancy. Single trough screening studies can provide quali-
tative estimates of elimination clearance, which with the dosing rate determines the
steady-state drug concentration, throughout pregnancy and into the postpartum period.
Population pharmacokinetic studies such as two stage pharmacokinetic studies and stud-
ies using a nonlinear mixed effects pharmacokinetic modeling approach can characterize
pharmacokinetic changes more rigorously.
Ó 2020 Elsevier Inc. All rights reserved.

There is a pressing need for studies of the pharmacokinetics
of drugs used in pregnant women, who have been poorly
represented in drug studies. The origin of the historical
under-representation of females of all ages in drug studies
has been attributed to concern about unnecessarily exposing
women of childbearing potential to drugs that followed the
thalidomide-induced phocomelia tragedy in the 1960s.1
While recognition of sex as an important variable in health
research by major organizations such as the Institute of Medi-
cine in 1991 stimulated the inclusion of women in clinical
trials,1,2 research to identify appropriate dosing, safety, and
effectiveness of medications in pregnant women has only
recently begun to be prioritized.3
Unfortunately, the effects of pregnancy on drug disposition
remain poorly understood due to lingering concerns about
the exposure of the unborn fetus to medications. As a result,
standard doses of drugs prescribed to pregnant women could
be subtherapeutic or toxic, if they are prescribed at all.4,5
To identify safe and effective dosing of a drug for the pregnant
woman, it is necessary to understand the effect of the bio-
chemical and physiologic changes in pregnancy on the dose-
response relationship of the drug. Such studies are urgently
needed6 and optimal dosing information derived from them
must be translated it into “the right dose for the right condition
in the right patient.”7 The Obstetric-Fetal Pharmacology
Research Centers (OPRC) Program was established by the
Eunice Kennedy Shriver National Institute of Child Health and
Human Development (NICHD) in 2004 to enhance the under-
standing of dose-response relationships in pregnant women.
Research supported by the OPRC has included clinical studies
in pregnant women that identify the longitudinal changes of
the dose-response relationship in pregnancy.4
The goal of this report is to review pharmacologic concepts
that form the basis of optimal drug prescribing and their appli-
cation to pharmacotherapy, beginning with a consideration of
the dose-response relationship. It then reviews several

E-mail address: mja190@northwestern.edu

https://doi.org/10.1016/j.semperi.2020.151227
0146-0005/Ó 2020 Elsevier Inc. All rights reserved.
2 S E M I N A R S I N P E R I N A T O L O G Y
approaches to studying the pharmacokinetics of a drug in the
various stages of pregnancy and the postpartum period.
The dose-response relationship
The earliest statement of the dose-response relationship was
provided by Philippus Aureolus Theophrastus Bombastus von
Hohenheim (1492
1541), who is perhaps better known as Par-
acelsus. In his Third Defense, this remarkable Swiss physician
and alchemist said, “. . . what is there that is not poison, all
things are poison and nothing (is) without poison. Solely the
dose determines that a thing is not a poison.”8 A contemporary
statement of the dose-response relationship has been taught
in graduate school as Tatum’s (presumably Arthur Lawrie
Tatum, 1884
19559) Dictum, “The dose of a drug is enough.”
Every physician aspires to prescribe their patients a dose that
will produce the therapeutic effect while avoiding toxicity.
What determines the dose that is enough? How and why would
a dose that is enough in an individual when they are not preg-
nant be too much or too little when they are pregnant?
The dose-response relationship is determined by pharma-
cokinetics (drug absorption, distribution, and elimination or
what the body does to a drug) and pharmacodynamics (the
relationship between drug concentration and the effect it pro-
duces or what the drug does to a body)10 (Fig. 1). Biochemical
and physiologic changes that occur in pregnancy could affect
the pharmacokinetics or pharmacodynamics of a drug and
thus affect its dose-response relationship. This review will
focus on the pharmacokinetic aspects of the dose-response
relationship. The interested reader is referred for detailed
presentations of general and specific aspects of clinical phar-
macology to the authoritative textbook on pharmacokinetics,
Principles of Clinical Pharmacology, written and edited by Arthur
J. Atkinson, Jr. and colleagues.11
Pharmacokinetics
As an introduction to the fundamental concepts of pharmaco-
kinetics, two seminal studies of the pharmacokinetics of thio-
pental will be considered, one here in the Pharmacokinetics
Fig. 1 – The dose-response relationship is determined by
pharmacokinetics, or what the body does to a drug, and
pharmacodynamics, or what a drug does to the body.
Modified from Sheiner and Tozer.10
44 (2020) 151227
section and one later in the Drug Accumulation section. These
studies provide important insights into the distribution of a
typical lipophilic molecule. For several decades the barbiturate
thiopental was administered by intravenous injection to pro-
duce anesthesia. It has a very rapid onset of effect and a very
brief duration of action that was initially thought to be due to
its irreversible removal from the body by hepatic metabolism12
and later thought to be due to uptake by fat, which is faster
than its metabolism.13 Price and colleagues demonstrated that
its hypnotic effects are actually terminated by redistribution
from the brain, its site of action, to pharmacologically unaf-
fected tissues, such as muscle.14 This is nicely illustrated in
Fig. 2, which shows that drug concentrations in the blood, into
which it has been infused (the central pool), decrease precipi-
tously as a result of distribution to highly perfused, rapidly
equilibrating tissues of the viscera, including the heart, kidney,
splanchnic area, and brain. Slower distribution occurs to the
less well perfused but high capacity lean tissues and to the
poorly perfused adipose tissues (fat). The brisk distribution of
thiopental from the blood to the brain produces the rapid
onset of its effect. Once drug concentrations in the tissues of
the viscera and brain reach equilibrium with those in the blood
(the peak visceral concentration occurs at approximately
1 min in Fig. 2), they begin to decline as those in the blood
(pool) continue to decrease. Meanwhile, the concentrations in
the lean and fat tissues continue to rise at the expense of the
viscera and brain. This redistribution of drug from the brain
and other well perfused viscera to the lean tissues and fat
ends the effect of this “ultra-short acting” drug on the brain.
After drug concentrations in the lean tissues have reached
equilibrium with those in the blood (the peak lean concentra-
tion occurs at approximately 32 min in Fig. 2), concentrations
in the lean tissues begin to decrease while those in the brain
and viscera further decline and the concentrations in adipose
tissues continue to rise.
These insights into drug distribution were based on tissue
drug concentration measurements. Although tissue drug con-
centrations are not typically measured in contemporary clini-
cal pharmacokinetic studies, plasma drug concentrations are.
Fig. 2 – Price’s physiologic pharmacokinetic mode of thio-
pental distribution from the pool (intravascular space) to the
viscera (which includes the brain, where the drug produces
its hypnotic effect), lean tissue, and, ultimately, fat after
rapid intravenous administration. Reprinted from Price
et al.14 with permission.
 TAGEDENS E M I N A R S I N
When blood samples are obtained frequently and serially
after drug administration, the dynamic processes of distri-
bution and redistribution described by Price and colleagues
are reflected in the exponential phases of plasma thiopental
concentration versus time relationships15 (Fig. 3). A very
rapid decrease in plasma drug concentration is observed
during the distribution phase, which begins the moment the
drug is administered intravenously. Within a matter of
minutes, the transition into the redistribution phase, during
which drug concentrations decrease more slowly, is evident.
The drug redistribution phase lasts several hours before
transitioning into a slower, terminal, elimination phase.
Because the body is in distributional equilibrium during the
elimination phase, the concentration of drug in plasma
changes only as a result of the irreversible removal, or elimi-
nation, of drug from the body. A drug and its metabolites, if
any, are typically eliminated from the body by hepatic
metabolism, renal excretion, or both.
This disposition (i.e., distribution and elimination) of a drug
can be described by a mathematical model that characterizes
the plasma drug concentration versus time relationship using
a three compartment pharmacokinetic model (Fig. 4). In a
three-compartment pharmacokinetic model, the central or
initial volume of distribution (VC) is the volume in which a
drug is assumed to mix instantaneously before being distrib-
uted throughout the remaining volume. From VC, drug is dis-
tributed to the rapidly (fast) and slowly (slow) equilibrating
volumes of distribution (VF and VS, respectively) by intercom-
partmental clearance (ClI). Intercompartmental clearances
between VC and both the rapidly equilibrating and the slowly
equilibrating volumes (ClF and ClS, respectively) are volume-
independent estimates of drug transfer that are determined
by blood flow and transcapillary permeability. These varia-
bles are measured in units of volume per unit time. The
volume of distribution at steady-state (VSS) is the sum of the
volumes of the central, rapidly equilibrating, and slowly
equilibrating compartments.
Elimination clearance (ClE) is a concentration-independent
quantitation of the ability of the body to remove drug, and has
units of volume per unit time. It can be thought of as the por-
tion of the drug distribution volume from which drug is
Fig. 3 – The disposition of a thiopental viewed from the
plasma after rapid intravenous administration, illustrating
the rapid distributional phase, the redistribution phase, and
the terminal elimination phase. Modified from Fragen and
Avram.15
P E R I N A T O L O G Y 44 (2020) 151227 3
Fig. 4 – The three compartment mammillary pharmacoki-
netic model in which drug enters the central compartment
(volume VC) and immediately begins equilibrating with the
rapidly equilibrating (fast) peripheral compartment (volume
VF) and the slowly equilibrating (slow) peripheral compart-
ment (volume VS) by their corresponding intercompartmen-
tal clearances (ClF and ClS). As the distribution processes
begin, the body also begins eliminating the drug by elimi-
nation clearance (ClE).
irreversibly removed per unit time. Unlike ClE, the elimination
rate of a drug at any given time is concentration-dependent. It
is the product of the ClE and the plasma concentration of the
drug at that time.
The clearance of a drug by an organ is a function of both
blood flow to the organ (Q) and the efficiency with which the
clearing organ removes drug from the blood, the extraction
ratio (E). It can, therefore, be affected by factors affecting
blood flow to the organ or by factors affecting the efficiency
of the organ in removing the drug, such as hepatic enzyme
induction or inhibition. Thus, hepatic elimination clearance
(ClH) can be described as16
ClH ¼ Q H ¢ EH
Drugs cleared by the liver can be classified as high (EH > 0.7),
intermediate (EH = 0.3 to 0.7), or low (EH < 0.3) EH drugs. Drugs
with a high QH have flow-limited hepatic ClE because their EHs
are minimally affected by physiologic perturbations. The ClH of
drugs with low EHs have capacity-limited clearance because it
is not affected by changes in QH. Factors, such as the biochemi-
cal and physiologic changes of pregnancy, producing changes
in either QH or the EH of drugs with intermediate EHs can affect
the ClH of these drugs.
Renal clearance is affected by glomerular filtration, tubular
secretion, and tubular reabsorption. Glomerular filtration
depends on both renal blood flow and the efficiency with
which the glomeruli filter the drug (the extraction ratio),
which change in pregnancy. In non-pregnant adults, renal
blood flow is generally less variable than hepatic blood flow
because it is autoregulated and is, therefore, less likely to be
rate limiting in drug clearance. Because only unbound drugs
are filtered, a slight decrease in the protein binding of an
extensively (> 90%) bound drug that is eliminated by glomer-
ular filtration will increase its glomerular filtration rate.
The elimination half-life (t1/2b) is the time required for the
amount of drug in the body to decrease by 50%. The t1/2b of a
4 S E M I N A R S I N P E R I N A T O L O G Y 44 (2020) 151227

drug is a dependent variable that is related directly to a

model-independent estimate of its volume of distribution
(Vdb) and inversely to its ClE:
t1=2b ¼ 0:693 Vdb =ClE

Drug accumulation and bioavailability

The longer the duration of an intravenous drug infusion, the

closer the concentrations in the tissues come to reaching
equilibrium with the drug in the blood. As drug accumulates
in tissues during continuous administration, they lose their
dilutional capacity after termination of drug administra-
tion.17 That is, plasma concentrations decrease less rapidly
after stopping a drug infusion than they do after rapid intra-
venous administration. Therefore, for example, the time
required to recover from an infusion of thiopental increases
with the duration of the infusion (Fig. 5).
The accumulation of drug as a result of equilibration of
drug in the blood with the tissues during infusion or multi-
ple-dose regimens occurs until a steady-state is achieved. At
steady-state, all compartments are in equilibrium, no net tis-
sue distribution occurs, and the infusion rate (I) exactly
matches the elimination rate. The steady-state plasma drug
concentration (CSS) is predictable from these variables:
CSS ¼ I=ClE
The approaches of plasma drug concentrations to CSS for a
continuous constant rate intravenous infusion and an inter-
mittent constant rate oral administration are illustrated in
Fig. 6.18 When the drug is administered by a continuous con-
stant rate intravenous infusion, the plasma drug concentra-
tions increase steadily until they plateau at the CSS after an
infusion lasting more than four t1/2bs (called half-times in
Fig. 6). Continued infusion at the same rate would maintain
that CSS unless there is a change in the ClE of the drug.
The accumulation of a drug during repeated oral administra-
tion at intervals equal to the t1/2b of the drug is illustrated by the
plasma drug concentration versus time relationship that
Fig. 5 – The rates at which thiopental leaves the brain by
redistribution to indifferent tissues after rapid intravenous
administration (Rapid Inj) and after 20 min, 60 min, and
120 min infusions. Reprinted from Price17 with permission.
Fig. 6 – The approach of plasma drug concentrations to the
steady-state concentration (CSS) for a continuous constant
rate intravenous infusion and intermittent constant rate
oral administration. Reprinted from Buxton18 with permis-
sion.
oscillates around the smooth increase in drug concentrations
produced by a constant infusion at the same rate (Fig. 6). After
each oral dose, drug concentrations increase from the predose
trough during the absorption phase until a maximum concentra-
tion is reached (Cmax) for the dosing interval at time Tmax. After
this point the concentrations decrease as a result of redistribu-
tion and elimination. Oral dosing achieves a CSS that is the aver-
age of the peak and trough concentrations after constant rate
(e.g., the same dose administered every t1/2b) oral administration
lasting more than four t1/2bs. Like continuous intravenous
administration, continued oral administration at the same rate
maintains that CSS unless there is a change in the ClE of the drug.
As suggested above, administration of drug by any route other
than intravenous adds additional complexities to the pharmaco-
kinetics of the drug, such as the rate of drug absorption. An addi-
tional complexity is the bioavailability of the drug, F, which is
the extent of absorption or the fraction of the dose reaching the
systemic circulation after administration. An intravenously
administered drug has a bioavailability of 1 because all of the
drug administered enters the systemic circulation. The bioavail-
ability of a drug administered by nearly any other route is usu-
ally less than 1 because some portion of the dose administered
does not enter the systemic circulation. In the case of an orally
administered drug, its bioavailability may be affected by incom-
plete absorption, intestinal metabolism, or first-pass metabo-
lism by the gut wall and liver. First-pass refers to the absorption
of drugs from the intestinal lumen through the gut wall and into
the portal circulation, which flows directly to the liver where
they may be metabolized before entering the systemic circula-
tion. A high hepatic extraction ratio for a drug reduces its bio-
availability. For orally administered drugs, pharmacokinetic
equations containing the terms dose or dosing rate must make
an adjustment for its bioavailability. For an orally administered
dose, the steady-state concentration is determined by the bio-
available dosing rate and the elimination clearance:
CSS ¼ ððDose  FÞ=t Þ=ClE
 TAGEDENS E M I N A R S I N
where t is the dosing interval (e.g., the t1/2b dosing interval in
the example in Fig. 6). Bioavailability is determined by compar-
ing the area under the curve of the plasma drug concentration
versus time relationship of a dose after administration by a
non-intravenous route with that of the dose after intravenous
administration. Such studies are often done in the same indi-
viduals to whom drug is administered by each route on sepa-
rate occasions. When a stable isotopically labeled formulation
is available for oral or intravenous use, the two routes can be
studied simultaneously. This approach eliminates not only
interindividual differences in drug disposition by the two
routes being compared but also interday differences in drug
disposition in the same individuals.19
The need for pharmacokinetic studies in
pregnancy
The dose-response relationships of drugs taken by a woman
before she becomes pregnant are likely to change when she
becomes pregnant. If she has been taking a dose of the drug
on a regular basis, that dose may become ineffective or
result in new side effects. Changes in the dose-response
relationship in pregnancy are due to changes in the pharma-
cokinetics or the pharmacodynamics of the drug (or both).
Much of what is known about the alterations in the dose-
response relationship of drugs in pregnancy has focused on
changes in the steady-state concentration, which may
change due to decreased bioavailability, increased elimina-
tion clearance, or both.
Drug distribution throughout the body, including to the site
of drug action, occurs as a result of mixing, flow, and diffu-
sion, which are affected by cardiovascular physiology.20,21
Irreversible removal of drugs from the body (ClE) occurs pri-
marily by enzymatic metabolism and renal elimination,
which are affected by factors ranging from blood flow to hor-
monal enzymatic induction or inhibition. Physiologic
changes that occur throughout pregnancy and can affect the
pharmacokinetics of drugs include increases in cardiac out-
put, hepatic blood flow, and glomerular filtration rate. Such
physiologic changes as well as pregnancy-induced changes in
drug metabolizing enzymes, such as increases in CYP3A4,
CYP2D6, and UGT1A4 activity and decreases in CYP1A2 activ-
ity, have been reviewed elsewhere22
25 (Fig. 7). The result of
many of these changes is an enhanced ClE, with a resulting
decrease in both CSS and therapeutic effectiveness as has
been reported for antiepileptic agents,23 antiretroviral
drugs,26 antidepressants,27 and other drugs.28
Another important element of pharmacokinetics is drug
absorption from the gastrointestinal tract. Since many, if not
most, drugs are administered orally, the decrease in gastric
pH, prolonged gastric emptying, and reduced gastric motility
in pregnancy could affect the rate and extent of drug absorp-
tion.29 Similarly, increased dermal hydration and increased
skin blood flow affects transdermal drug absorption.29
The dynamic physiologic and biochemical changes that
occur across pregnancy are associated with the timing of
alterations in drug pharmacokinetics. To develop optimal
dosing strategies throughout pregnancy and after birth when
physiologic changes are reversed, longitudinal studies must
P E R I N A T O L O G Y 44 (2020) 151227 5
be conducted to identify the time course of alterations in the
pharmacokinetics and pharmacodynamics of drugs.
Population pharmacokinetic studies
Population pharmacokinetic approaches are well-suited to
identifying changes that occur during pregnancy.30 The goal
of population pharmacokinetics is to characterize inter-indi-
vidual, intra-individual, and inter-occasion variability in drug
pharmacokinetics and explain the observed variability. Fac-
tors such as patient characteristics, gestational timing, co-
morbid diseases, and concomitant medication can affect the
pharmacokinetic parameters of a drug. The two most com-
mon population pharmacokinetic strategies are the two-stage
and the nonlinear mixed effects modeling approaches. In
designing a pharmacokinetic study to test hypotheses such
as that ClE is increased or decreased in pregnancy, published
data describing the pharmacokinetics of the drug in nonpreg-
nant individuals can help plan blood sampling for plasma
drug concentration measurements. Sample collection during
the absorption, distribution, and elimination phases is critical
to careful characterization of pharmacokinetics. For a
detailed discussion of not only population pharmacokinetics
but also population pharmacodynamics, the interested
reader is referred to an excellent series of articles by Mould
and Upton.31
33
Studies for the two-stage approach need to be data rich for
all subjects each time they participate (e.g., each trimester
and postpartum). Blood samples need to be obtained before
drug administration and then frequently during the absorp-
tion, distribution, and elimination phases. Each set of the
individual subject’s concentration versus time data is first
modeled using nonlinear regression to obtain an estimation
of pharmacokinetic parameters for each time they were stud-
ied (the first stage). Individual parameter estimates for each
stage of pregnancy and postpartum are then combined to
generate mean population parameters along with their vari-
ance and covariance to explain the observed variability (the
second stage).
When plasma drug concentration data are collected from
individuals using a sparse sampling strategy (i.e., one to six
drug concentrations are available per subject), parameter
estimates for individuals are not possible. However, if the
samples are collected in a carefully planned manner from a
relatively large number of individuals during the various
pharmacokinetic phases, a non-linear mixed effects model-
ing approach can be used. This approach estimates the popu-
lation pharmacokinetic parameters and their relationship to
covariates from the concentration versus time data and char-
acteristics of interest of all of the participants in the study.
The disposition of beta-blockers in pregnancy has been stud-
ied using both the two stage modeling approach and non-lin-
ear mixed effects modeling. Hebert et al. studied the
pharmacokinetics of atenolol in 17 patients in the second and
third trimesters of their pregnancy and three months postpar-
tum using a two stage pharmacokinetic approach.34 They
found that its renal clearance in the second and third trimes-
ters were 38% and 36% higher than postpartum renal clear-
ance, respectively. and was strongly correlated with creatinine
6 S E M I N A R S I N P E R I N A T O L O G Y 44 (2020) 151227

Fig. 7 – Physiologic changes in pregnancy that can affect the absorption, distribution, and elimination (metabolism and
excretion) of drugs. CL = elimination clearance, F = bioavailability, AUC = area under the drug concentration vs. time relation-
ship, t1/2 = elimination half-life, ln2 = 0.693, Vd = model-independent volume of distribution, Css = steady-state concentration,
t = dosing interval, Tmax = time to maximum plasma concentration (Cmax) after administration of a dose, CYPs = cytochrome
P450 enzymes, UGTs = uridine 50 -diphospho-glucuronosyltransferases, and GFR = glomerular filtration rate. Reprinted from
Tomson et al.23 with permission.

clearance. However, the total oral ClE/F of atenolol did not
change during pregnancy. The oral ClE/F of the high EH drug
labetalol was studied in 57 women from the twelfth week of
pregnancy through 12 weeks postpartum by Fischer et al.
using nonlinear mixed effect modeling.35 They reported its
ClE/F at 12 and 40 weeks gestational age was 40% and 60%
higher than postpartum, respectively. Lean body weight was
the only covariate retained in the final model of labetalol ClE/F.
Single trough screen studies
Elimination clearance determines the CSS achieved by a dose
of a drug administered chronically, and the ClE of certain drugs
is expected to change in pregnant patients. A simpler study
design, the single trough screen, could be used to provide qual-
itative estimates of ClE throughout pregnancy and into the
postpartum period. In the single trough screen, one blood sam-
ple is obtained from each patient at or near the trough during
steady-state dosing, shortly before the next dose is adminis-
tered, for plasma drug concentration measurement. A fre-
quency distribution of trough plasma drug concentrations pro-
vides a fairly accurate picture of the variability in trough con-
centrations, and, by inference, the ClE, in the population of
interest. The sample size should be sufficiently large (20 or
more patients studied multiple times during pregnancy and
postpartum), assay and sampling errors small, and the dosing
regimen and sampling times identical for all patients. The rela-
tionship of patient characteristics to the trough concentrations
can be explored by simple statistical procedures. Plasma drug
concentration to dose ratios can be used in lieu of plasma con-
centrations if the study participants are taking different doses.
An example of such a study is one designed to determine how
soon lamotrigine ClE changes in pregnancy.36 Blood samples of
convenience (rather than trough samples) were collected from
22 participants during 25 pregnancies before conception and
every two weeks between 5 and 13 gestational weeks.
Increased lamotrigine ClE was present at 5 weeks gestation but
the relationships of changes in ClE to serum estradiol concen-
trations and to gestational week were not strong enough to be
used clinically because of the significant interpatient variabil-
ity that is commonly observed in studies of this design.
 TAGEDENS E M I N A R S I N
Physiologically based pharmacokinetic modeling
Physiologically based pharmacokinetic (PBPK) modeling has
been a rapidly growing field for more than a decade. Such
modeling integrates physiological, physicochemical, and
drug-dependent data in a complex mathematic model that is
used to simulate the absorption, distribution, metabolism,
and excretion of a drug under a variety of conditions.37 In so
doing, it is able to simulate the drug concentration versus
time relationships in arterial and venous blood in vascular
beds throughout the body and in a large number of tissues.
Physiologically based pharmacokinetic models are becoming
an increasingly important part of drug discovery and develop-
ment in the pharmaceutical industry where they have been
used to do everything from informing study design to facili-
tating drug approval and labeling.38 A pregnancy module
incorporating time-varying physiology of pregnancy using a
commercially available simulator was introduced in 2013.39
Published physiologically based pharmacokinetic pregnancy
models have been reviewed recently, with a discussion of
their many strengths and several limitations as well as identi-
fication of needed refinements.40 Application of a physiologi-
cally based pharmacokinetic modeling and simulation to
predict an optimal dose of darunavir/ritonavir in pregnancy
nicely illustrates the utility of such models in the absence of
formal pharmacokinetic studies.41 The predicted dose is
being tested in patients and the results of the testing will be
used to refine the model.
Closing thoughts
Conducting studies of the pharmacokinetics and pharmaco-
dynamics of drugs in pregnancy involves clinicians, patients,
clinical pharmacologists, analytical chemists, and statisti-
cians. Clinicians are needed guide the selection of diseases
and medical treatments to be studied and assess patient
characteristics, safety, and effectiveness. Carefully selected
patients taking the drug of interest and willing to participate
in the study multiple times throughout the course of their
pregnancies (e.g., in each of their trimesters) and postpartum
(e.g., at two weeks and one or two months postpartum) are
essential for longitudinal studies. Clinical pharmacologists
help design the studies and analyze and interpret the data.
Analytical chemists measure a wide range of drug concentra-
tions in biological matrices with great precision and accuracy.
Biostatisticians provide invaluable input into the design,
analysis, and interpretation of complex longitudinal studies.
The studies described above have varying degrees of diffi-
culty and provide answers with different degrees of com-
pleteness. When one wishes to know whether pregnancy
affects the pharmacokinetics of a drug, qualitative estimates
of ClE throughout pregnancy and into the postpartum period
can be obtained by a single trough screening study, which is
relatively easy to conduct and requires a moderate number of
subjects. If a qualitative change in the pharmacokinetics of a
drug is discovered in a single trough screening study, a fol-
low-up population pharmacokinetic study could be con-
ducted to characterize the pharmacokinetic change more
P E R I N A T O L O G Y 44 (2020) 151227 7
rigorously. A two stage pharmacokinetic study can be con-
ducted in ten to twenty individuals but requires the collection
of a relatively large number of samples over up to 24 h from
each individual on each occasion, which may necessitate
admission to a Clinical Research Unit. A nonlinear mixed
effects pharmacokinetic modeling approach requires fewer
blood samples be collected from each individual using a
sparse sampling strategy on each occasion, but often necessi-
tates the study of up to 100 or more subjects. Physiologic
pharmacokinetic modeling can be used to facilitate the effi-
cient design of population pharmacokinetic studies.
Pariente et al. conducted a systematic review of 198 studies
of the pharmacokinetics of 121 medications in pregnancy.42
They found that pharmacokinetic changes during pregnancy
were often consistently observed among studies, including
the increased ClE along with the resultant decrease in drug
exposure for a given dose of many drugs. What they often
found missing was the very important consideration of
whether a dose adjustment was necessary to compensate for
the observed pharmacokinetics changes, which is, presum-
ably, the point of conducting such studies. When suggesting
a dose adjustment to be tested in a prospective clinical trial,
changes in not only dose but also dosing strategies should be
considered. For example, if an increase in dose is recom-
mended to offset an increase in ClE, dosing the drug more fre-
quently may be warranted to avoid substantial increases in
peak concentrations that could be associated with adverse
effects not seen pre-pregnancy.
Many of the physiologic changes of pregnancy, including
those that may lead to an increase in dose requirements,
return to normal after delivery over variable lengths of time.
Studying drug disposition is imperative not only during preg-
nancy but also when their physiology has returned to the
non-pregnant baseline to identify when the increased dose of
pregnancy is no longer needed.
Disclosures
Michael J. Avram, Ph.D., is the Assistant Editor-in-Chief of
Anesthesiology and on the Editorial Board of Clinical Pharmacol-
ogy & Therapeutics. He is a co-investigator on several NIH
grants, including NICHD U54 HD085601 “Optimizing Medica-
tion Management for Mothers with Depression during Preg-
nancy (OPTI-MOM)” CoPIs: Katherine Wisner, M.D., M.S.,
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