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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5195_Библиотеки_им_академика_М_И_Перельмана.pdf
1994;50:97–8.
IMPACT OF MATERNAL DISEASE: CONFOUNDING BY
INDICATION
While some infectious agents are teratogenic, noninfectious maternal disease
conditions may have an impact on fetal development and/or normal
functioning, modifying an association between a drug exposure and an
outcome (e.g., diabetes mellitus). This factor, known as confounding by
indication, is another reason why teratogenicity of drug is difficult to assess,
although there are ways to minimize this bias, including a control group with
the same indication but without drug exposure, or with a different indication.
DRUGS IN LACTATION
Breastfeeding is a standard method for feeding for most infants, but infant
safety of maternal medication use and exposures to nonmedicinal compounds
including environmental toxins is an important clinical issue. Here, we
describe key pharmacologic elements essential for safety assessment of those
maternal exposures during breastfeeding.
EPIDEMIOLOGY OF MATERNAL MEDICATION USE
DURING BREASTFEEDING
Although the majority of women initiate breastfeeding,56 in developed
countries, more than half of them require medication.
57,58
Safety-risk balance
in these circumstances is difficult to evaluate because basic information on
PK in milk is often lacking. This is in part due to noninclusion of pregnant as
well as breastfeeding patients in the drug development processes. The lack of
PK data in milk continues after marketing. As a result, poor adherence
occurs,59 and unnecessary discontinuation or noninitiation of breastfeeding is
observed.
60,61
Given the tangible benefits of human milk,
62–72
consequences of
the information gap appear substantial, although they may not be readily
recognized. On the other hand, reports of serious infant toxicity through
breastfeeding by women on drugs or other substances continue to emerge.
73,74
TABLE 10.5
BENEFITS OF BREASTFEEDING
When drug safety during lactation is assessed, benefits of human milk for both
mother and infant must be made explicit.62 The evidence of the benefits is
generated mostly from cohort studies and epidemiologic analyses, as
randomized trials are not possible under most circumstances. However,
biologic plausibility and frequently observed associations between
breastfeeding and various health benefits support the presence of causal
relationship. Table 10.5 lists those benefits, including infection resistance and
better cognitive development in the infant.
62,64–68,71,72
Also, maternal benefits
have been observed, including reduced rates of malignancies affecting the
reproductive organs.
75,76
Benefits of Human Milk
Outcome Parameters Associated with Breastfeeding
Compared to Formula
Feeding/Nonbreastfeeding
Rates of infection in the infant
Acute otitis media 50% lower
Lower respiratory infection 70% lower
NEC 80% lower
Gastroenteritis 60% lower
Inflammatory bowel disease 30% lower
Obesity 20% lower
SIDS 40% lower
Cognitive function of the infant
IQ 8 points higher
Rates of malignancies in the mother
Breast cancer 60% lower
Ovarian cancer 30% lower
NEC, necrotizing enterocolitis; SIDS, sudden infant death syndrome.
Data from Johnston M, Landers S, Noble L, et al. Breastfeeding and the use of human milk.
Pediatrics 2012;129:e827–e841 and Stuebe A. The risks of not breastfeeding for mothers and
infants. Rev Obstet Gynecol 2009;2:222–231 and Collaborative Group on Hormonal Factors in Breast
Cancer. Breast cancer and breastfeeding: collaborative reanalysis of individual data from 47
epidemiological studies in 30 countries, including 50302 women with breast cancer and 96973 women
without the disease. Lancet 2002;360:187–195.
CELLULAR MECHANISM OF DRUG EXCRETION INTO
MILK
The mammary gland epithelia are comprised of the ducts and the secreting
alveoli, surrounded by contractile myoepithelial cells.
77,78
These secretory
systems and blood vessels are contained in the interstitium of the breast
tissue, forming a drug excretion unit.
Lactation is regulated by the hypothalamo–pituitary–mammary axis.
Prolactin stimulates milk synthesis by alveolar cells, whereas milk ejection
by myoepithelial cells is stimulated by oxytocin. Within this pathway,
dopamine is an important inhibitory factor of the release of prolactin.
Multiple mechanisms exist for drug excretion into milk, including passive
and facilitated diffusion and active transport.79 Also, during exocytosis,
vesicles are formed that contain newly synthesized proteins and lactose, as
well as water and electrolytes, including small molecule drugs in the
cytoplasm. Once excreted into a milk compartment, slightly acidic pH in milk
compared to maternal plasma makes cationic compounds to be more ionized
in milk than plasma, preventing them from freely diffusing back to plasma
through lipid bilayers. This phenomenon of ion trapping of cationic
compounds in the milk compartment explains relatively high milk-to(maternal) plasma concentration ratio (MP ratio) of basic drugs. Other factors
that may increase MP ratio include low plasma protein binding and high
lipophilicity of drug. As described later, however, MP ratio by itself does not
fully define the level of infant drug exposure through milk. Therefore,
selecting medications for breastfeeding women, based only on relatively low
values of MP ratio alone, has little clinical significance.
A complete picture of mammary drug excretion remains to be fully
elucidated, particularly regarding carriers involved in transport. However, a
combined model of diffusion and breast cancer resistance protein (BCRP)—
mediated efflux into milk explains milk disposition profiles of BCRP
substrate drugs, including cimetidine and nitrofurantoin.
80–84
This model of
combined diffusion and active transport indicates importance of both
diffusion-related factors (e.g., ionization characteristics, plasma protein
binding, and lipophilicity, as described above) and substrate specificity to the
transporter such as BCRP in defining drug excretion into milk.
BCRP is highly induced in the lactating mammary gland epithelia, as an
efflux transporter reducing exposures to drugs and toxins.82 High-level
expression and function are also observed in tissues of barrier function,
including vascular endothelial cells in the brain (i.e., blood–brain barrier),
placental syncytiotrophoblast, and intestinal epithelia. Importantly, the
lactation-associated induction of mammary gland BCRP is specific to the
mammary gland responding to a lactation-related prolactin surge in plasma
and resultant activation of the JAK2/STAT5 pathway.85 While BCRP is known
for toxin excretion function in general, its role in the mammary gland appears
to be the transporter for vitamin B2 (riboflavin),84 which is enriched in milk.
In contrast to BCRP, other ATP-binding cassette transporter P-glycoprotein
(ABCB1) and MRP1 (ABCC1) are downregulated during lactation.
83
PHASES OF MILK EXPRESSION
Milk composition varies depending on temporal profiles within the feeding
(i.e., foremilk vs. hindmilk) and across the entire breastfeeding period (i.e.,
colostrum, transition milk, and mature milk). Foremilk is defined as milk
expressed at the beginning of a feeding. Milk toward the end of a feeding is
called hindmilk. From a pharmacologic point of view, the foremilk–hindmilk
distinction is important with regard to the relative composition of the milk.
Namely, foremilk is rich in lactose, and hindmilk is rich in lipid fractions.
Lipophilic drugs may achieve higher concentrations in hindmilk than in
foremilk, assuming that other properties of milk remain the same, such as pH.
Because it is difficult to mimic actual feeding in experimental settings of milk
PK studies, description of how milk was collected is considered practical
and sufficient. Colostrum is milk during the first few days of the postpartum
period, which is rich in immune cells and factors. For ethical reasons, milk
PK studies are rarely performed using colostrum, and because milk intake is
not so high during the first couple of days, drug exposure through milk is
relatively small during the colostrum period. In general, mature milk is used
for milk PK research.
RELATIVE INFANT DOSE AND MILK-TO-PLASMA
CONCENTRATION RATIO
There are two PK indices that are useful in characterizing drug disposition in
milk: relative infant dose (RID or %RID) and milk-to-(maternal) plasma drug
concentration ratio (MP ratio).
The MP ratio indicates a drug concentration in milk relative to that in
maternal plasma and is expressed as a ratio of AUC (area under the curve)
between milk and maternal plasma.79 As a simplified surrogate, a single time
point is often used to derive MP ratio. However, concentration–time profiles
may be different between milk and maternal plasma, rendering this approach
grossly inaccurate. This parameter represents a relative concentration of the
drug in milk in relation to maternal plasma/serum, providing information on
drug disposition across the mammary gland epithelia. As described below,
interpretation of MP ratio requires caution because it is a ratio and not an
absolute concentration of drug in milk.
MP ratio is sometimes misinterpreted as a single determinant of the infant
drug exposure level.73 For example, MP ratio of greater than 1 indicates
accumulation of the drug in milk relative to maternal plasma concentration and
often interpreted as an indicator of toxic exposure. However, this
interpretation is not necessarily correct because infant exposure levels to drug
in milk are determined by not only MP ratio but also drug clearance.
73
While MP ratio relates drug concentrations in the two distinct
compartments (i.e., milk and maternal plasma), RID (or %RID) relates infant
dose of the drug via milk-to-maternal therapeutic doses on a weight basis. It is
a weight-adjusted, time-averaged (e.g., daily) dose of drug in milk the infant
would take, expressed as a fraction or a percentage of the time-averaged
therapeutic dose on a body weight basis. RID (or %RID) of 100% is the same
as receiving a full therapeutic dose per weight; RID 10% means that infant
receives the drug in milk at 10% of the therapeutic dose per body weight.
TABLE 10.6
RID (also known as %RID) of 10% is often viewed as a safety threshold
for dose-dependent effects in risk assessment,79 but some consider 5% as a
threshold of compatibility for psychoactive drugs.86 Distribution of RID
among the current therapeutic drugs indicates that RID is 10% or lower for
most drugs. The exceptions are those with relatively low CL (<1 mL per kg
per minute, such as phenobarbital, ethosuximide, and lithium), which result in
relatively high RID (20% to 50% of the levels of exposure at therapeutic
doses),73 but this does not mean that they are contraindicated in breastfeeding
because risk–benefit analyses are specific to circumstances of individual
patients.
These cutoff values (i.e., RID of 5% to 10%) are not thresholds of toxicity
but rather theoretical reference points for risk assessment. Although infant
drug exposure through milk should be compared to a neonatal therapeutic dose
as a reference point, rather than a maternal dose, information on neonatal
therapeutic doses is often unknown.
PHARMACOKINETICS OF DRUG IN MILK
RID is a function of MP ratio and CL as described below.73 Table 10.6
summarizes definitions of some parameters necessary to derive key PK
equations of drug disposition in milk.
Pharmacokinetic Paramete rs of Drug Excretion in Milk
Parameter (Symbol) Definition
Infant dose (ID) Amount of drug the infant ingests via milk/body
weight/day
Mother’s dose (MoD) Mother’s dose of drug/body weight/day
Milk volume (MV) Milk volume for an infant/body weight/day
Drug concentration in milk ([C]
milk
) and in
maternal plasma ([C]
plasma
)
Average drug concentration at steady state over
a 24-h period.
Relative infant dose (RID or %RID) ID divided by MoD, expressed as percentage
Milk-to-plasma concentration ratio (MP ratio) AUC (area under the curve) ratio between milk
and maternal plasma
By definition described above, infant dose (ID) of the drug through milk is:
Because [C]
milk
can be also expressed as a product of MP ratio and
[C]
plasma
,
Replacing ID in the above formula with Equation (1),
At steady state, [C]
plasma
can be expressed as:
where F is bioavailability and CL is total body clearance of the drug in the
mother. Therefore, Equation (2) can be rewritten as:
Assuming that F = 1, RID can be rewritten as a percentage parameter:
MV of an infant is usually assumed to be 150 mL per kg per day (about 0.1
mL per kg per minute).
79,87
Therefore,
where the unit of CL is mL per kg per minute.
Figure 10.1 shows Equation (3) as the logarithmic relationship between
CL and RID (RID can be depicted as “exposure index”,73 because they are
equivalent by definition) in three MP ratio categories. Because observed MP
ratios and CL show limited ranges of values, drugs are distributed into a
relatively confined space. For example, reported MP ratios of most drugs are
around 1 or lower, and most drugs have a clearance of greater than 1 mL per
kg per minute,88 indicating that most drugs are in the shaded area of Figure
10.1. In addition, it is noted that RID dependence on MP ratio is pronounced
for drugs with relatively low CL; drugs with low CL (e.g., <1 mL per kg per
minute) have relatively high RID, which is further accentuated if their MP
ratios become high due to intra- or interindividual variations. Therefore,
clinical significance of MP ratio to define RID depends on maternal CL of the
drug. In other words, most drugs are unlikely to achieve RID of greater than
10%, but those with low CL (e.g., <1 mL per kg per minute) may achieve
higher RID, especially if MP ratio is high.
Figure 10.1 Percent relative infant dose (%RID) as a logarithmic function of clearance and milk-to-
plasma concentration (MP) ratio. %RID is infant dose of drug through milk (mg per kg per day)
expressed as a percentage of a weight-adjusted therapeutic dose of drug in the mother. With three
different MP ratio scenarios (0.2, 1, and 5), the graph shows Equation (3) (see text) in a logarithmic
scale, which defines %RID as a function of MP ratio and maternal drug clearance. The shaded area
indicates a space where most drugs belong. Note that drugs with relatively low clearance (e.g., <1 mL
per kg per minute) tend to achieve high %RID compared to high clearance drugs. Also, variations in MP
ratio have more significant impact on %RID in low clearance drugs.
Figure 10.2 contrasts a high CL drug with a low CL drug, illustrating a
higher degree of MP ratio dependence of RID in low CL drug than in high CL
drugs. In clinical settings, this indicates that inter- or intraindividual
variations of MP ratio have a bigger impact on RID of low CL drugs,
compared to high CL drugs.