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TABLE 10.1
Shinya Ito
Ruud Verstegen
C H A P T E R
10
Maternal Medications During Pregnancy and Lactation
PHARMACOKINETIC CHARACTERISTICS IN
PREGNANCY: ITS IMPLICATIONS IN FETAL
DRUG EXPOSURE
Medication use in pregnancy poses two main pharmacologic challenges:
pharmacokinetics (PK) changes during pregnancy and fetal drug safety. In this
chapter, we provide an overview on these two aspects.
MATERNAL PHYSIOLOGIC CHANGES OF PREGNANCY
Pregnancy is associated with drastic changes in hemodynamics, including
fluid volume expansion, vasodilation, and hyperperfusion (i.e., increased
blood flow to most organs, except for the brain). The percentage increase in
water compartment sizes during pregnancy is in the range of 30% to 40% from
the prepregnancy levels.
1–4
Increase in blood/plasma volume, heart rate, and
stroke volume contributes to nearly 40% rise of cardiac output5 and resultant
increase in blood/plasma flow to drug-eliminating organs (Table 10.1). In
addition, glomerular filtration rate (GFR) increases,
6–8
and intrinsic activity of
some drug-metabolizing enzymes in the liver changes during pregnancy.
9,10
Along with decreased plasma protein binding, these changes cause alterations
in the PK parameters of many drugs.
Main He modynamic and Physiologic Change s in Pregnancy
Parameter Change (Prepregnancy →
Peak Level in Pregnancy)
References
Body weight +15% (60 kg → 70 kg)
Cardiac output +40% (5 L/min → 7 L/min)
Robson et al.
5
Organ blood/plasma flow
Moran et al.,6 Nakai et al.
21
Total liver blood flow (portal
vein plus hepatic artery)
+50% (2 L/min → 3 L/min)
Renal plasma flow +50% (0.6 L/min → 0.9 L/min)
Drug elimination systems
Odutayo and Hladunewich,
7
Cheung and Lafayette,
8
Pariente et al.
30
Liver:
Intrinsic hepatic metabolism Variable (enzyme specific)
Biliary excretion Not well characterized
Kidney:
Glomerular filtration rate +50% (120 mL/min → 180
mL/min)
Net tubular secretion Not well characterized
(transporters)
Volume compartment
Lukaski et al.,1 Van Loan et
al.,2 Silver et al.,3 Wadsworth
4
Total blood volume +40% (4L → 5.7 L)
Plasma volume +40% (2.8L → 4 L)
Total body water +30% (32L → 40 L)
Extracellular fluid +30% (15L → 20 L)
Plasma protein
Notarianni14, Chen et al.
17
Albumin −20% (47 g/L → 38 g/L)
α-1-Acid glycoprotein −30% (0.7 g/L → 0.5 g/L)
Gastrointestinal function
Wald et al.,11 Lawson et al.,
12
Chiloiro et al.
13
Gastric emptying time Unchanged
Gastrointestinal transit time Prolonged
Gastrointestinal motility also changes during pregnancy. Gastric emptying
time remains relatively unchanged during pregnancy, but total gastrointestinal
transit time (mouth-to-cecum) is longer in pregnancy than in nonpregnant state,
suggesting that intestinal transit time is prolonged significantly.
11–13
This may
increase oral bioavailability of some drugs, which do not undergo intestinal
metabolism, although its clinical significance may not be obvious.
During pregnancy, total plasma protein concentrations decrease,14 and
colloid osmotic pressure is reduced.15 Although concentrations of some
proteins such as globulins are increased,14 concentrations of major drugbinding proteins (i.e., albumin and α-1-acid glycoprotein) are decreased in
pregnancy, leading to an increased fraction of unbound drug (fu).
14–17
The
impact of an increased fu on total and free (unbound) drug concentrations
varies among drugs, depending on the magnitude of the increase and the
elimination characteristics of the drug.
PHARMACOKINETIC PARAMETER CHANGES
Pharmacokinetic Determinants of Plasma Drug Concentration at Steady
State
In order to predict the impact of pregnancy-associated physiologic changes on
drug concentration–time profiles, it is important to understand PK
determinants of drug concentrations in plasma at steady state. A simplified
picture of their relation is described below on the assumption of a onecompartment model with instant distribution. Note that precise interpretation
of PK theories is outside the scope of this chapter.
First, at a given dose (D) and a dosing interval (τ), plasma clearance (CL)
and oral bioavailability (F) define an average concentration of drug at steady
state ([C]
mean
), but volume of distribution (Vd) does not influence [C]
mean
; the
higher the CL, the lower the [C]
mean
.
Note that drug concentrations and PK parameters here are based on total
drug concentrations in plasma (i.e., bound plus unbound), unless stated
otherwise. The ratio of CL to Vd also defines an elimination rate constant (k),
and an elimination half-life (t
1/2
) is a function of k: the higher the CL, the
shorter the t
1/2
; the larger the Vd, the longer the t
1/2
.
The two primary parameters (i.e., CL and Vd) and their ratio (k or ln2 /
t
1/2
) are mathematically interdependent, and if any two of the three parameters
are known, then one can calculate the remaining one. However, CL and Vd are
physiologically determined independent parameters, while k and t
1/2
depend
on these two parameters because it is a ratio of the two. Therefore, k and t
1/2
may be viewed as secondary parameters. These secondary parameters cannot
be primarily altered without changing one of the two primary parameters: CL
and Vd. Also, the mathematical relationship (CL = Vd × k) is correct but only
on a mathematical term. Physiologically, CL is not dependent upon Vd and
vice versa.
Second, at steady state during repeated dosing (e.g., every 12-hour oral
dose), Vd determines an amplitude of a rise from a trough ([C]
min
) to a peak
concentration ([C]
max
); the larger the Vd, the smaller is the difference between
[C]
max
and [C]
min
. As described before, changes in Vd per se do not affect
[C]
mean
, but CL changes do.
Third, CL through a main drug-eliminating organ can be expressed as a
function of plasma protein binding [i.e., unbound fraction (fu), blood flow rate
(Q), and intrinsic clearance (CL
int
)], according to the well-stirred model. In