BACKGROUND
Ideally, pharmacologic agents would not be needed during
pregnancy; however, some women enter pregnancy with medical conditions that
require ongoing or episodic treatment (e.g., asthma, epilepsy, hypertension).
During pregnancy, new medical problems can also develop, and old ones can be
exacerbated (e.g., migraine headaches), requiring pharmacologic therapy.
Studies have shown that most pregnant women do use either prescribed or
over-the-counter medications during pregnancy (Bonati 1990, De Vigan 1999,
Lacroix 2000, Mitchell 2001). Interviews of approximately 20,000 U.S. and
Canadian women conducted over 25 years reported a mean of 2.3 medications used
during pregnancy, excluding vitamins and minerals (Mitchell 2001).
Of the women
interviewed, 28 percent reported using more than four medications during
pregnancy, and medication use increased with maternal age. In addition, the
mean number of medications taken, in successive 5-year intervals, progressively
increased from 2.7 to 4.4, indicating secular patterns of medication use by
pregnant women. A comparison of therapeutic drug use during pregnancy in Europe
showed that 64 percent of women used at least one drug during pregnancy (De Vigan 1999), while in France, pregnant women were prescribed an average of five
drugs during the first trimester (Lacroix 2000).
Generally, the safety and efficacy of a drug are
established for a particular dosage regimen or range of dosage regimens in late
phase (Phase 3) clinical trials involving relatively typical representatives
from the target patient population. Pregnant women are actively excluded from
these trials, and, if pregnancy does occur, the usual procedure is to
discontinue treatment and drop the patient from the study. Consequently, at the
time of a drug’s initial marketing, except for products developed to treat
conditions specific to pregnancy (e.g., oxytocics, cervical ripening agents),
there are seldom human data on the appropriate dosage and frequency of
administration during pregnancy. Even after years of marketing, data in product
labels regarding PK and dose adjustments during pregnancy rarely provide more
information for appropriate prescribing in pregnancy than was available at the
time of initial marketing.
The few data to address appropriate dosage and frequency of
administration in pregnancy are not usually supported by a full understanding of
the alterations of the PK of the drug in pregnancy. For example, the majority
of published PK studies of anti-infective drug products during pregnancy were
conducted at the time of abortion or delivery (usually via cesarean section) and
were done to determine the transplacental passage of drug. In the absence of
data, the usual adult dose is typically prescribed for pregnant women. Because
of the physiologic changes inherent in pregnancy, the result can be substantial
under dosing, or, in some cases, excessive dosing.
Extrapolation of PK data from studies performed in
nonpregnant adults fails to take into account the impact of the many physiologic
changes that occur during pregnancy. Most of the physiologic changes manifest
during the first trimester and peak during the second trimester of pregnancy.
Physiologic changes are not fixed throughout pregnancy but rather reflect a
continuum of change as pregnancy progresses, with return to baseline at various
rates in the postpartum period. The physiologic changes have the potential to
alter the PK and/or PD of drugs. Some of these changes include:
·
Changes in total body weight and body fat composition.
·
Delayed gastric emptying and prolonged gastrointestinal transit
time.
·
Increase in extra cellular fluid and total body water.
·
Increased cardiac output, increased stroke volume, and elevated
maternal heart rate.
·
Decreased albumin concentration with reduced protein binding.
·
Increased blood flow to the various organs (e.g., kidneys,
uterus).
·
Increased glomerular filtration rate.
·
Changed hepatic enzyme activity, including phase I CYP450
metabolic pathways (e.g., increased CYP2D6 activity), xanthine oxidase, and
phase II metabolic pathways (e.g., N-acetyltransferase).
A significant amount of pharmacologic research has been
conducted to improve the quality and quantity of data available for other
altered physiologic states (e.g., in patients with renal and hepatic disease)
and for other patient subpopulations (e.g., pediatric patients).
The need for PK/PD studies in pregnancy is no less than for these populations,
nor is the need for the development of therapeutic treatments for pregnant
women.
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