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this chapter, we approximate CL as plasma clearance and Q as organ plasma
flow. Note that this scheme does not fully address the bioavailability and
intestinal metabolism in oral drug administration and the potential impact of
additional factors including the fetoplacental unit on plasma clearance of
drugs. Although further refinement of such a theoretical model is necessary,
the simple scheme facilitates our conceptual understanding of the pregnancyassociated changes in drug concentration profiles.
Efficiency of drug elimination is expressed as extraction ratio (ER),
ranging from 0 to 1.
If (fu × CL
int
) is sufficiently higher than Q, ER approaches the maximum
value of 1, which is the characteristic of high ER drugs (i.e., ER > 0.7). In this
case, CL almost equals and becomes highly dependent on Q, as long as high
ER status is maintained. For high ER drugs, if Q increases by a factor of 0.5
(i.e., 50% increase), such as in pregnancy (and if [fu × CL
int
] is not
significantly decreased), then CL will increase by nearly 40% to 50%.
Because physiologic increase in Q of the liver and kidney in pregnancy is
within a range of about 1.5-fold, it will not alter the high ER status of the drug.
This CL increase occurs irrespective of their elimination routes, unless
responsible transporters and/or drug-metabolizing enzymes are significantly
downregulated.
On the other hand, if (fu × CL
int
) is sufficiently smaller than Q, then ER
becomes far lower than 1 (i.e., ER = [fu × CL
int
]/Q), which defines low ER
drugs (i.e., ER < 0.3). For these low ER drugs, CL equals (fu × CL
int
), and
increases of Q have no impact on CL, but changes of (fu × CL
int
) do. As
discussed later, drugs that are mainly eliminated via GFR from the kidney are
low ER drugs (because GFR represents CL
int
that is much smaller than renal
plasma flow), and therefore, their CL is elevated in pregnancy due to
pregnancy-associated GFR increase (by 50%) and fu elevation (the magnitude
depends on drugs). For low ER drugs mainly metabolized by the liver, CL
int
represents each of the enzymatic processes unique to the respective drugs, and
therefore, their CL changes during pregnancy become drug specific. In
addition, overall reduction of plasma protein binding leads to an increase in
fu, which becomes a factor to increase CL of low ER drugs. These two
examples above are extreme ends of the spectrum, and there are drugs in the
intermediate ER category (e.g., ER: 0.3 to 0.7), which show mixed patterns.
On the whole, pregnancy-associated PK changes stem from (a) increased
organ blood/plasma flow to the liver and kidney, the main drug-eliminating
organs; (b) increased fu due to lower plasma protein concentrations; (c)
increased GFR; and (d) increased sizes of water compartments. Intrinsic
activity changes of hepatic drug-metabolizing enzymes (i.e., CL
int
of the
enzyme) are variable and enzyme specific. Also, pregnancy-associated
changes of transporter expression in renal tubular cells are not well
understood. With some exceptions, the above changes tend to result in
decreased [C]
mean
due to increased CL, and a smaller amplitude between
[C]
max
and [C]
min
due to increased Vd. As described before, changes in k and
t
1/2
are dependent on CL and Vd. The clinical implications of these PK changes
will be illustrated by examples later.
The simple conceptual understanding described above is not sufficient for
accurate description of the observations in vivo. For this purpose,
physiologically based PK modeling is necessary, which is outside the scope
of this chapter.
Drugs Metabolized by the Liver
Hepatic Blood/Plasma Flow
The liver receives blood supply from two systems: the hepatic artery and the
portal vein. Although food intake alters their relative contribution to total
liver blood flow,
18,19
about one-third of total liver blood flow is from hepatic
artery, and the remaining two-thirds are from portal vein.
20–22
Total hepatic
blood flow measured by Doppler ultrasonography reaches approximately 3 L
per minute in the third trimester (>50% increase from the prepregnancy level,
Table 10.1), mainly due to significant increase in portal venous blood flow.
21
While this is consistent with the overall increase in cardiac output during
pregnancy, liver blood flow estimated from clearance of indocyanine green
(ICG)23 or bromsulphalein (bromsulphthalein, BSP)24 does not show
significant pregnancy-associated increase.
Both ICG and BSP are substrates for hepatic uptake transporters
25,26
and
have a high ER.27 Their clearance depends mainly on hepatic blood flow, at
least in nonpregnant women and male subjects. Reduced function of uptake
transporters for ICG/BSP during pregnancy is likely to result in lower ER,
which has been shown in animal experiments.28 In addition, the presence of
endogenous substances during pregnancy, such as progesterone metabolites,
interferes with the transporters.29 ICG and BSP may not represent flowdependent high ER compounds during pregnancy. Therefore, it is fair to
assume that total liver blood/plasma flow is significantly increased during
pregnancy as the imaging studies using Doppler ultrasonography
demonstrated.
21,22
Table 10.2 presents CL changes of drugs during pregnancy,30 according to
the three categories of ER. Assuming that total liver blood/plasma flow is
increased during pregnancy by 50% to 60%, one may expect similar increases
in CL of drugs metabolized by the liver with high ER, unless responsible
uptake systems and/or metabolizing enzymes are significantly downregulated,
such as the case of ICG and BSP described above. Although CL increase
often gives an impression of increased “intrinsic activity” of respective drugmetabolizing enzymes, increase in liver blood/plasma flow during pregnancy
is likely to be the main mechanism for those high ER drugs. It is also
important to note that this flow-dependent CL increase occurs in any
enzymatic system as long as the ER is high. Examples include metoprolol
(CYP2D6 substrate) and indinavir (CYP3A4 substrate), which show 50% to
100% increase in CL and resultant decrease in steady-state serum
concentrations during pregnancy.
31–34
Although the pregnancy-associated
increase in their CL and resultant reduction in serum concentrations can be
explained mainly by increased liver blood flow, minor changes in the intrinsic
enzyme activity may exist. In contrast, some high ER drugs, such as
propranolol (CYP1A2 and CYP2D6 substrate),
35,36
do not show clear
increase in CL during pregnancy.30 This is likely a result of reduced intrinsic
activity of the enzyme (e.g., CYP1A2 for propranolol) or transporters during
pregnancy as discussed below.
Clearance Changes during Pregnancy
TABLE 10.2
Intrinsic Activity of Drug-Metabolizing Enzymes and Plasma Protein
Binding
CL of a low ER drug depends on the product of intrinsic activity of
responsible enzymes (CL
int
) and fu, and therefore, changes in [CL
int
× fu] are
reflected on CL changes. Lamotrigine is a low ER drug, and its plasma protein
binding is also not high. Therefore, the reported CL increase during
pregnancy30 is likely a result of significant increase in CL
int
(i.e., increased
expression of UGT1A4), which is consistent with the findings from
experiments of humanized UGT1 mice.37 Phenytoin is a CYP2C9 substrate
with low ER but has relatively high plasma protein binding. Phenytoin CL
during pregnancy is increased by an average of 40% as well as fu by about
20%.30 Because its oral bioavailability remains unchanged in pregnancy,38 CL
increase in phenytoin may indicate an increase in both unbound fraction and
intrinsic activity of hepatic CYP2C9. Carbamazepine, a CYP3A4 substrate, is
another low ER drug with an fu of 0.2 (i.e., 80% bound). During pregnancy, its
fu may increase by about 50% to 0.3,39 which is likely to account for the
relative increase of its CL of 10% to 30%.30 However, a small increase in
intrinsic activity of CYP3A4 may coexist.
Pregnancy-associated increases in CL are also reported in other CYP3A4
substrates, such as midazolam.
40,41
They are characterized by intermediate ER
(midazolam 0.43) and relatively high plasma protein binding (>95%).42 This
suggests that CL of midazolam is dependent on all three factors (i.e., organ
blood flow, protein binding, and intrinsic activity of CYP3A4). For example,
pregnancy-associated relative increase in midazolam CL is about 1.8- to
twofold from the nonpregnant level for both intravenous and oral
administration.
40,41
Because the 50% increase in liver plasma flow in
pregnancy cannot account for the entire twofold increase in midazolam CL, it
is likely that [CL
int
× fu] is also increased substantially, but evidence is scarce
to define the relative contribution of fu and CL
int
increase (i.e., CYP3A4
activity).
By contrast, CL of caffeine, a CYP1A2 substrate, is decreased in
pregnancy.10 Because it has a low-intermediate ER with low plasma protein
binding, its CL decrease is likely a result of decreased CYP1A2 activity.
Whether this is due to decreased expression or other factors has yet to be
determined, but it provides a clue to the fact that propranolol, which is a high
ER drug in nonpregnant state and a partial CYP1A2 substrate, does not show
elevated CL in pregnancy.
30
Drugs Eliminated from the Kidney
Renal Plasma Flow
Hemodynamics of normal pregnancy is characterized by volume expansion,
vasodilation, and increase in organ blood flow. Renal blood/plasma flow
reaches a peak of about 140% compared to the prepregnancy level in the first
and second trimesters, before gradually returning to the prepregnancy level in
the early postpartum period.7 For drugs mainly eliminated through kidney, the
processes of glomerular filtration and net secretion (i.e., secretion minus
reabsorption) are equivalent to CL
int
according to the well-stirred model.
Because normal GFR (100 to 120 mL per minute) in the nonpregnant state is
much lower than renal plasma flow (500 to 700 mL per minute), GFRdependent drugs without net secretion are low ER drugs. Conversely, drugs
with high ER through renal elimination must have significant tubular secretion,
which overwhelms reabsorption processes, causing substantial net secretion.
Pregnancy-associated increase in renal plasma flow raises the CL of drugs
with relatively high ER, such as metformin. Metformin is eliminated through
kidney via filtration and net tubular secretion
43,44
and shows no appreciable
plasma protein binding. Renal CL of metformin is as high as renal plasma
flow, indicating its high ER. Renal CL of metformin rises by nearly 50% in
mid-pregnancy and by 30% in late pregnancy,
45,46
which is consistent with the
time profile of renal plasma flow change in pregnancy.
7
Filtration and Net Secretion
In contrast to high ER drugs such as metformin, GFR-dependent drugs with no
or minor net secretion are low ER drugs because GFR (i.e., CL
int
) is much
smaller than renal plasma flow (Q); therefore, its CL is insensitive to plasma
flow increase but depends on changes in fu and CL
int
.
Increase in GFR during pregnancy is observed as early as in the first
trimester. In the second and third trimesters, it reaches 150% of the
prepregnancy level (e.g., 120 mL per minute in prepregnancy and 180 mL per
minute in the second and third trimesters; Table Table 10.1). Note that this
time profile is different from that of renal plasma flow, which shows a peak
increase in mid-pregnancy.7 As a result, CL of drugs, which are eliminated
mainly through kidney by filtration such as amoxicillin (low-intermediate ER),
becomes significantly higher in the second and third trimesters (>50%
increase), which is consistent with the profile of GFR change. Digoxin is
another example, showing similar changes.
Drug Concentrations in Plasma and Clinical Impact
The PK changes in pregnancy described above often lead to decreased drug
concentrations in plasma, with some exceptions. Given that the fu is usually
increased in pregnancy, reduced total drug concentrations (bound plus
unbound drug) somewhat offset an increased fu, thereby unbound drug
concentrations (not the fraction) may remain relatively unchanged compared
to nonpregnant state. Although this suggests that plasma concentrations of
pharmacologically active drug molecules (i.e., unbound) remain unchanged,
there are clinical examples of reduced therapeutic effects.
Because pregnancy is not only characterized by PK changes but also
alterations in disease courses and drug responses, clinical consequences of
the PK changes are difficult to predict. Data are slowly accumulating,
nonetheless. For example, pregnancy-associated PK changes of lamotrigine
(increased CL and decreased [C]
mean
) were reportedly associated with
unfavorable clinical outcomes.
47,48
For antimicrobial drugs including anti-HIV
drugs such as indinavir, failure to achieve target plasma concentrations is a
major concern in the treatment of pregnant patients.32 Another example are
atazanavir-, elvitegravir-, or darunavir-cobicistat combinations for anti-HIV
treatment. These anti-HIV protease inhibitors are CYP3A4 substrates. In
order to acquire adequate plasma concentration profiles, cobicistat is
coadministered as a PK enhancer by blocking CYP3A4. Although cobicistat
is not extensively metabolized and its PK is complex, plasma concentrations
of cobicistat become low in pregnant patients.49 The failure of CYP3A4
inhibition results in substantial increase in CL and decreased [C]
mean
of these
anti-HIV protease inhibitors. Because of this, instead of teratogenic effects on
the fetus, the combination is considered a contraindication during pregnancy.
DRUG SAFETY IN PREGNANCY
THE THALIDOMIDE DISASTER
In November 22, 1961, at the meeting of West German Pediatricians,
Widukind Lenz, a pediatrician in former West Germany, reported the outbreak
of phocomelia (i.e., reduction defects of the limbs) in infants exposed in utero
to thalidomide that was used as a sedative to relieve symptoms of morning
sickness during pregnancy. Followed by the letter to the editor in the Lancet
by an Australian obstetrician, William McBride, published on December 16,
TABLE 10.3
1961, the “thalidomide” disaster became widely recognized, leaving more
than 10,000 infants worldwide to face the consequences of the rare birth
defects. The hardship of the survivors of this tragedy marks one of the darkest
moments in the history of pharmacotherapy. Thalidomide was then withdrawn
from the market, but later reintroduced and presently used for other
indications, including multiple myeloma, as an immune modulator. In the past,
thalidomide was also used to control a leprosy complication known as
erythema nodosum leprosum. Although this is no longer a recommended
practice, inadvertent exposure during pregnancy continues to occur, posing
significant challenges to drug regulation.
TERATOGENICITY OF DRUG
A human teratogen is broadly defined as a medical condition, infection, or
substance that causes harm to an embryo (10 weeks’ gestational age or 8
weeks’ postconceptional age) and/or fetus (Table 10.3). Data obtained in
developed countries indicate that the prevalence of congenital anomalies of
all causes is about 2% to 4% of live births.
50–53
Because of the background
occurrence of fetal abnormality in the absence of intrauterine exposures to
drugs, signal detection of drug-induced fetal toxicity is challenging.
Teratogenicity of thalidomide and some others such as isotretinoin for
intractable acne can be recognized relatively easily because their signals of
fetal adverse effects are very high compared to the background occurrence.
This is due to their characteristic fetal toxicity (i.e., phocomelia for
thalidomide and ear plus other facial deformity for isotretinoin), which is
considered highly specific to the intrauterine exposures to these drugs in the
first trimester. As a result of their extremely low background occurrence, the
toxicity signals of these exposures become distinct and pathognomonic. In
contrast, if a resultant abnormality is not specific (e.g., ventricular septal
defect, which is a relatively common congenital heart defect), it is more
challenging to confirm exposure–defect causality in individual cases.
Major Human Teratogens
SHEPARD CRITERIA
The teratogenicity criteria proposed in 1994 by Thomas Shepard set a
foundation for assessment of fetal drug toxicity (Table 10.4).54 The seven-item
criteria for proof of human teratogenicity are an amalgamation of several
other criteria and deeply embedded in the framework of Hill criteria for
causation. The first criterion stipulates a presence of proven exposure within
the critical period of organ development in question because vulnerable
periods of fetal development differ among different organs, although the first
trimester is often the most vulnerable period for malformations. The second
criterion describes required consistency/reproducibility of the findings, which
TABLE 10.4
should have a sufficiently high effect size of the signal of abnormality.
Although the original Shepard criteria proposed a relative risk of 6
(compared to the nonexposure) as a necessary signal for a teratogen, smaller
risks of 1.5 to 3 in well-executed studies may be considered sufficient as a
clinically meaningful attribute of a teratogen. The third criterion calls for
clear definition of resultant phenotypes. The fourth criterion is an extreme
case of the spectrum, exemplifying a rare abnormality with a large effect size
(i.e., relative risk) and, therefore, considered as a special case of the second
criterion. A teratogen is expected to satisfy the criteria 1, 2, and 3 or criteria
1, 3, and 4. The remaining three criteria are nonessential but important
nonetheless, which include biologic plausibility and findings in animal
experiments. In addition to drug-associated fetal toxicity, the Shepard criteria
have been applied to positively identify Zika virus as a human teratogen.
55
Shepard Criteria for Teratoge nicity
1. Proven exposure to agent at critical time(s) in prenatal development (prescriptions, physicians’
records, dates).
2. Consistent findings by two or more epidemiologic studies of high quality
a. Control of confounding factors
b. Sufficient numbers
c. Exclusion of positive and negative bias factors
d. Prospective studies, if possible
e. Relative risk of six or more (?).
3. Careful delineation of the clinical cases. A specific defect or syndrome, if present, is very helpful.
4. Rare environmental exposure associated with rare defect. Probably three or more cases (e.g.,
oral anticoagulants and nasal hypoplasia, methimazole and scalp defects (?), and heart block and
maternal rheumatism).
5. Teratogenicity in experimental animals important, but not essential.
6. The association should make biologic sense.
7. Proof in an experimental system that the agent acts in an unaltered state. Important information
for prevention.
A teratogen is expected to satisfy the criteria 1, 2, and 3 or criteria 1, 3, and 4. The remaining
three criteria are nonessential.
Reprinted with permission from Shepard TH. “Proof” of human teratogenicity. Teratology