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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5195_Библиотеки_им_академика_М_И_Перельмана.pdf
Yet, busulfan conjugation by GSTA1-1 from intestinal biopsies appears to be
increased at 1 year of age and then slowly declines until adulthood. In
parallel, busulfan apparent oral clearance in vivo also shows an agedependent decrease.
104
The phase II DME also provides an illustrative example of compensatory
metabolism that occurs when primary drug metabolism pathways have yet to
fully develop. UGT1A6 and SULT1A1 are both responsible for primary
metabolism of acetaminophen. In the adult, the glucuronide metabolite is
recovered in majority with a glucuronide-to-sulfate ratio of 1.80 ± 0.32. In
contrast, the sulfate conjugate is recovered in majority in the newborn with
glucuronide-to-sulfate ratio of 0.34 ± 0.08, suggesting lack of full activity of
UGT1A6.
105
However, because SULT1A1 is a less efficient clearance
pathway, young infants have a longer acetaminophen half-live than do older
children and adults.
106
NON–PHASE I/PHASE II METABOLISM
Large molecules (e.g., biologics) are often metabolized by non–phase I and
non–phase II DMEs. Limited data are available on the role of ontogeny in the
clearance of large molecules; however, some assumptions can be made from
the examples that do exist. Factor VIII, a clotting cascade protein, is
associated with shorter half-lives in children 1 to 6 years of age (9.2 hours)
compared with older individuals 10 to 65 years (12.2 hours).
107
PK studies of
insulin, growth hormone, and erythropoietin demonstrate age-dependent
changes in clearance as well. Growth hormone has lower metabolic clearance
rates in prepubertal children compared with adult men and women.
108,109
Erythropoietin clearance is elevated in premature infants compared with
adults.
110
Insulin demonstrates higher systemic exposures in diabetic
adolescents compared with diabetic children with PK profiles that are
specific to the insulin isoform.
111–113
With a trend toward increased approval
and use of large molecule agents, an understanding of their distinct disposition
pathways and the impact of development is critical.
EXCRETION
Though excretion can occur through a variety of organ systems, the kidneys
are responsible for the majority of xenobiotic elimination. Passive filtration
occurs in the glomerulus, while secretion and reabsorption (both passive and
active) occur at the level of the proximal and distal tubule, respectively.
114
Developmentally, nephrogenesis is complete by 36 weeks of gestation;
however, maturation of the kidney continues well into childhood. The
newborn kidney contains the same number of nephrons as in adults
(~1,000,000 per kidney), yet is anatomically, morphologically, and
functionally distinguishable from the mature adult organ.
115
From birth to 12
years of age, the kidney undergoes nearly a doubling in length and
corresponding increase in weight, growth that is noticeable in the
microstructures as well. The average diameter of a glomerulus in a newborn
is approximately one-third of the adult. During the first 3 months of life, the
radius of small pores in the glomerulus increases from 19.6 to 25 Å (~25%
increase). During this period, the proportion of large pores relative to small
pores increases as well. Remarkable development of proximal tubules is also
observed. The average length of proximal tubules at birth is only one-tenth of
the adult (2 mm vs. 20 mm), and the variability in their length is much more
pronounced, with 11-fold difference between the shortest and the longest
measured proximal tubule in tissue samples versus twofold difference in
adult. Finally, increased vascular resistance and reduced renal blood flow
occur in the newborn with a subsequent increase in fractional cardiac output
to the kidney of nearly fourfold during the first year of life.
114,116
These age-dependent anatomic differences are, as expected, accompanied
by functional differences (Fig. 4.10). Glomerular filtration rate (GFR)
increases strikingly after birth and continues to increase until the completion
of growth in the child. However, when normalized to BSA, filtration appears
similar to that observed in adults within first 1 to 2 years.
117
Interestingly,
premature newborns have a significantly reduced GFR, which exhibits its
own developmental trajectory
118
(Fig. 4.11). With respect to tubular
reabsorption, urine concentrating ability is significantly lower at birth (600
mOsm per kg water), and it increases slowly to 900 mOsm per kg water
during the first month of life, ultimately reaching 1,200 mOsm per kg in
adolescence.
118
Figure 4.10 Changes in glomerular filtration (solid circles, solid line) rate and p-aminohippurate
clearance (open circles, dashed line) as a function of age. (Reprinted with permission from Brown JT,
Abdel-Rahman SM. Pediatric pharmacokinetics. Pediatric pharmacotherapy. Lenexa, KS: American
College of Clinical Pharmacy, 2013:26.)
Figure 4.11 Postnatal acquisition of functional renal filtration capacity as a function of gestational
age. (Reprinted with permission from Brown JT, Abdel-Rahman SM. Pediatric pharmacok inetics.
Pediatric pharmacotherapy. Lenexa, KS: American College of Clinical Pharmacy, 2013:26.)
The implication of these functional differences manifests as a significant
reduction in renal clearance, often resulting in a longer elimination half-lives,
for many renally cleared drugs. In premature infants, for example, the half-life
of fluconazole is 88 hours. In contrast, fluconazole half-life in term newborns
is reported in the range of 19.5 to 25 hours.
119
Vancomycin and amikacin
clearances are also reduced in premature infants and, irrespective of
gestational age, increase with postnatal age.
120,121
Typically, dosing is less
frequent (i.e., dosing interval is extended) for these medications in newborns
and infants in order to accommodate for the immature renal glomerular
filtration and maintain appropriate systemic exposures.
Age-dependent changes in clearance of p-aminohippurate (PAH), a
substrate for renal transport and marker of renal plasma flow, are also well
described. At birth, clearance of PAH is low and gradually increases until age
2 when the adult values are reached.
122
Whether this is the result of increasing
renal plasma flow or developmental changes in the expression of relevant
transporters (e.g., basolateral uptake OAT1/3 and apical efflux MRP2/4,
Table 4.2) is unclear. This finding signals that the complementary transport of
drugs may also change as a function of age. Recently, extensive information on
the ontogeny of human renal drug transporters residing in basolateral and
apical membranes of proximal tubule cells became available via quantitation
of these proteins in pediatric kidney tissues.
123
The expression of basolateral
uptake OAT1, OAT3, OCT2, and apical efflux P-gp transport proteins were
significantly reduced in term newborn and infants compared to children,
adolescents, and adults. On the other hand, expression of other apical efflux
transporters (e.g., MATE1, MATE2-K, BCRP, MRP2, MRP4) demonstrated
little age dependency. A summary of drugs that are representative substrates
of renal transporters is presented in Table 4.2.
124–127
Based on these findings,
it is reasonable to conclude which substrates may be susceptible to agedependent changes. However, it is important to note that a fraction of this
increase in renal clearance may also be due to concomitant maturation of
glomerular filtration function (as discussed above). Dedicated prospective
PK studies in children will help determine the extent of age-dependent PK and
appropriate dosing modifications for renal transport substrates that are
primarily excreted via the kidney. Given the important role of the kidneys in
maintaining electrolyte homeostasis, it is not unexpected to observe agedependent changes in expression and function of transporters mediating
passage of the electrolytes across the proximal tubule. The apically located
Na+/H+ and Cl–/OH– transporters and basolaterally located Na+/K+ ATPase,
as well as several different chloride transporters, show very reduced activity
in fetal and young animal models. The reduction in activity associated with
age appears to be due to the lower protein abundance along the entire length
of the nephron tubule in the young animals. To date, evidence implicating the
presence of unique transporter isoforms or different affinities for these
transporters during growth and development is lacking.
124,128–131
Hepatobiliary clearance serves as another route of excretion. As
discussed in the distribution section, a clear ontogenic profile has been
demonstrated for sinusoidally located hepatic OCT1 and OATP1B3
transporters. Importantly, immature functioning of transporters located on the
canalicular membrane of the hepatocyte is evident during the first few weeks
of life.
132
Investigations of age-dependent expression for canalicular
transporters of bile salts have, thus far, been most extensive for P-gp and
MRP2.35 Transcript and protein expression for both transporters have been
detected in 14-week-old fetuses. Compared with the adult, P-gp transcript
expression is approximately 20- to 30-fold lower in the fetus; however, a
rapid increase occurs in the first 12 months of life, bringing expression values
to within fivefold of the adult by 1 year of age. Importantly, mRNA and
protein expression for P-gp may not be concordant, since protein expression
levels of P-gp are reported to be constant between the ages of 1 month and 12
years,
35,133
or even through adulthood.
134
This finding was corroborated by a
separate study demonstrating relatively stable expression of P-gp protein in
livers from donors between 7 and 70 years old,35 although it is important to
note that the absence of age-dependent changes in P-gp expression has not
been uniformly reproduced.74 With regard to MRP2, relatively low mRNA
expression has been found in fetal tissue, followed by an increase in
expression seen after birth. The relative difference between fetal MRP2
mRNA and adult MRP2 mRNA is quite dramatic—approximately 200-fold. In
contrast, protein expression of MRP2 was either shown not to be affected by
age
74,134
or showed a reduced expression in infants less than 8 months of age
compared to children older than 12 years.35 Data on protein expression for
other efflux transporter proteins residing on the canalicular membrane are
similarly somewhat nonconsistent between studies; BCRP, BSEP, and MATE1
expression was shown not to be age dependent.74 A second study showed
distinct increased (BSEP) or decreased (BCRP) protein expression pattern
though smaller in sample size with reduced statistical power.
134
In following with developmental expression profiles, reduced biliary
excretion may be expected for drugs that are known substrates of hepatic
transporters, suggesting the need to consider dose adjustments in infants and
young children.35 Interestingly, renal clearance can compensate for this
reduction in biliary clearance for some drugs that are otherwise excreted into
the bile. For example, approximately 70% of the ceftriaxone dose is
recovered in the urine of neonates compared to older children and adults
(40% to 60%).
135
Analogous to ceftriaxone, the renal excretion of
1.
2.
3.
4.
5.
6.
7.
8.
9.
cefoperazone in premature infants is more extensive than in full-term neonates
(55% vs. 18%).
136
CONCLUSIONS
Once a drug enters the body of a child, its disposition is governed by
developmental physiology and pathophysiology. Successful and rational drug
dosing requires a comprehensive understanding of (a) the developmental
trajectories of enzyme and transporter function, (b) the physiology of a
growing and maturing body, and (c) the pathology of the underlying disease,
its presentation, and progression. Due to the existing gaps in knowledge (and
with limited data in the drug product label), clinicians are often presented
with a challenging task, to provide the best dosing recommendation for an
individual child. It is, therefore, imperative that the knowledge of underlying
mechanisms that govern drug disposition continues to expand, paving the way
for individualized pharmacotherapy in the neonate, child, and adolescent.
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