Pediatric Pharmacokinetics

Human Development and Drug Disposition

Ryan S. Funk, PharmD, PhDa, Jacob T. Brown, PharmD

a
,
Susan M. Abdel-Rahman, PharmDa,b,*

KEYWORDS

Pediatric
Pharmacokinetic
Development
Absorption
Distribution

Metabolism
Excretion
Transport

KEY POINTS

Drug disposition is dynamic and can be attributed to developmental physiologic changes.

An understanding of the anatomic and physiologic changes during development is para-
mount in predicting age-dependent changes in drug disposition.

Without a complete understanding of how biology drives drug disposition, pediatric clinical
pharmacokinetic studies are a necessity for rational drug use in children.

Future studies are needed to understand the ontogeny of drug disposition pathways,
including the importance of drug transporters, in pediatric clinical pharmacokinetics.

INTRODUCTION

The efficacious use of therapeutic agents is often guided by an understanding of the

relationship between dose and exposure (ie, pharmacokinetics [PK]). These relation-
ships vary based on the demographic, genetic, anthropomorphic, and pathologic
constitution of the patient being treated. As such, the clinical practitioner is required
to understand how these patient-specific factors influence the disposition of drugs
in the body. For pediatric practitioners, the process of growth and development over-
lays these patient-specific factors adding complexity to therapeutic management. In
the absence of pediatric PK studies to guide the safe and effective use of medications,
pediatric dosing can be guided by knowledge of the anatomic and physiologic factors
that govern drug disposition and the developmental patterns that influence these
factors.1

Disclosure: The authors have no competing financial interests.

a
Division of Clinical Pharmacology and Medical Toxicology, Children’s Mercy Hospitals and
Clinics, 2401 Gillham Road, Kansas City, MO 64108, USA; b Department of Pediatrics, School
of Medicine, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO
64108, USA
* Corresponding author. Division of Clinical Pharmacology and Medical Toxicology, Children’s
Mercy Hospitals and Clinics, 2401 Gillham Road, Kansas City, MO 64108.
E-mail address: srahman@[Link]

Pediatr Clin N Am 59 (2012) 1001–1016

[Link] [Link]
0031-3955/12/$ – see front matter Ó 2012 Elsevier Inc. All rights reserved.
1002 Funk et al

This article links understanding of anatomic and physiologic changes observed

during human development to their impact on drug disposition. It discusses develop-
mental changes that can affect the absorption, distribution, metabolism, and excretion
(ADME) of therapeutic agents in children. Relevant examples from the literature are
discussed and attention is drawn to developmental changes that have yet to be
described. Where human data are unavailable, animal data are supplemented to
allude to the potential role of ontogeny in drug disposition.

ABSORPTION

Drugs administered by extravascular routes must overcome multiple barriers to reach

the systemic circulation. In addition to the physical and chemical processes that affect
drug absorption (ie, stability, solubility, permeability), mechanical barriers such as
transporter-mediated uptake and efflux are being found to play an important role in
regulating the absorption of many drugs. All of these processes are influenced by
development, thus influencing the PK profiles of many drugs in children.

Peroral Absorption
Following oral administration, there are several ontogenic factors that influence
systemic drug absorption. One of the most prominent is the period of relative achlor-
hydria observed shortly after birth.2 Gastric pH influences absorption by 2 mecha-
nisms: permeation and stability. Although the stomach is not a principal site of drug
absorption, the decrease in ionization of weakly acidic drugs in the low-pH environ-
ment of the stomach can theoretically enhance permeation across the epithelial lining
of the stomach. In contrast, a decrease or delay in absorption could be expected for
weakly acidic drugs (eg, phenobarbital, phenytoin) under conditions of increased
gastric pH in the newborn.3–5 More importantly, the stomach is an important site of
pH-dependent drug degradation, ultimately affecting the amount of intact drug that
reaches the small intestine. Perhaps the best-documented example of the impact of
development on gastric pH arises with the acid-labile b-lactam antibiotic penicillin,
with which plasma concentrations in the neonate reach levels 5 to 6 times those
seen in infants and children owing to protection from decomposition (Fig. 1A).6
In contrast with the permeation-limited absorption of many water-soluble drugs,
oral absorption of many lipophilic drugs is limited by their poor solubility in the
aqueous digestive fluids. Absorption of drugs in this category often shows significant
food effects (eg, enhanced absorption in the fed state).7 Stimulation of bile acid secre-
tion into the alimentary canal by food results in micellar solubilization of many lipophilic
drugs rendering their absorption dependent on biliary function. Despite an increase in
circulating bile acid levels in young infants, concentrations of the major bile salts in the
intestinal lumen are reduced, likely the result of a decrease in transporter-mediated
secretion of bile acids into the biliary canaliculi.8,9 As a result, clinically significant
changes in drug absorption are possible for solubility-limited drugs. This possibility
is shown by data on the antiviral pleconaril, a highly lipophilic compound that, in
adults, shows a 2-fold increase in exposure with food.10 Although dose escalation
studies in adults revealed a dose-proportional increase in exposure, dose escalation
in neonates resulted in no increase in exposure.11 This failure to increase neonatal
drug exposure may reflect restricted bioavailability caused by limited micellar solubi-
lization. If so, then other solubility-limited, lipophilic drugs may have similar saturable
absorption profiles in neonates.
In addition to the impact of the gastrointestinal fluid composition on the solubility
and permeability of drugs, the rate of gastric emptying (GE) influences the speed at
 Pediatric Pharmacokinetics 1003

Fig. 1. (A) Penicillin plasma concentrations following the oral administration of a single
22,000 units/kg dose in neonates, infants, and children. (B) Age-dependent enteral absorp-
tion of iron expressed as a percentage of the dose administered.

which drugs are presented to the absorptive surfaces of the small intestine. The rate of
GE is prolonged in the first week of life and approaches adult values by 6 to 8 months
of age.4,12 There exists a significant level of developmental variation in GE, in part
because a variety of newborn disorders can significantly affect GE rates, among
them prematurity, respiratory disease, gastroesophageal reflux disease, and congen-
ital heart disease. Intestinal motility further affects the drug’s residence time, thereby
serving as another important determinant of the rate and extent of drug absorption.13
In the young infant, intestinal contractile frequency and amplitude are reduced and
highly variable.14 The overall impact of decreased emptying and motility on drug
absorption depends on the dissolution and permeation properties of the formulation.
For drugs that are rapidly and completely absorbed within the small intestine, absolute
bioavailability in young infants is expected to remain mostly unchanged, although the
rate of absorption, and consequently the maximum drug concentration (Cmax), may be
significantly reduced and the time to Cmax (Tmax) delayed. Age-dependent changes in
the absorption rate constant (ka) and Tmax for numerous drugs and nutrients (eg, L(1)-
arabinose, phenobarbital, sulfonamides, digoxin, cisapride) support this hypothesis.4,15
1004 Funk et al

Attempts to enhance absorption rates in young infants via administration of a prokinetic

agent can increase ka; however, absolute differences in the absorption rate constants
between neonates (<30 days of life) and infants (>30 days of life) remain unchanged
despite pharmacologic stimulation.4 These results suggest that additional develop-
mental factors influence the rate of drug absorption in the neonate.
Apart from physicochemical and mechanical forces, phase I and phase II drug
metabolizing enzymes (DME) residing in the intestinal tract influence drug absorption.
Although only limited data exist on the age-dependent expression of most intestinal
DMEs, existing data support a developmental component for at least some of the
enzymes. Duodenal biopsies have shown increases in intestinal CYP1A1 and
CYP3A with increasing age.16,17 Thus, drugs metabolized by these pathways are ex-
pected to undergo less presystemic intestinal clearance in young children. Among the
intestinal phase II enzymes evaluated to date, glutathione S-transferase (GST)–medi-
ated conjugating capacity of the antineoplastic agent busulfan was highest in distal
duodenal biopsies from children less than 5 years of age compared with children older
than 8 years of age and adolescents.18 These findings are in accordance with age-
dependent changes in the presystemic clearance of this drug, implying that young
children may require higher oral doses of drugs that are subject to clearance via gluta-
thione conjugation. With the paucity of data on the ontogeny of intestinal DMEs,
further studies are needed to fully examine the influence of development on intestinal
drug metabolism.
One of the newest and still emerging fields is the study of the impact of drug trans-
porters on absorption. Transporter proteins expressed along the intestinal tract not
only facilitate the uptake of nutrients and drugs across the intestinal epithelium but
also limit their absorption by actively pumping them back into the intestinal lumen.
As with intestinal DMEs, very few data have been generated on developmental
changes in transporter expression, and the studies that have been completed are
primarily restricted to the transport of nutrients (ie, SGLT1, GLUT2, PEPT1) in animal
models, many of which seem to be maximally expressed shortly after birth.19 By
contrast, the acquisition of iron absorption capacity (mediated by DMT1) increases
linearly after birth, reaching adult levels by early childhood (see Fig. 1B).20,21
Among established drug transporters, it seems that P-glycoprotein (P-gp) is present
in the intestine by 1 month of age.22 Other PK studies provide circumstantial evidence
supporting developmental changes in intestinal drug transporter activity. For example,
the H2-receptor antagonist nizatidine (a substrate for intestinal transporters whose
activity can be modified by the coadministration of apple juice) shows an age-
dependent decrease in apparent oral clearance despite no age dependence on
terminal elimination rate constant.23,24 Even transporters whose expression seems
to mature shortly after birth can show age effects.25 Drugs whose transport is medi-
ated by the intestinal peptide transporter 1 (PEPT1) compete with milk peptides for
uptake,26 and infants on a milk-based diet with condensed feeding frequency likely
have milk peptides continuously distributed along the intestinal lumen. Thus, the ma-
gnitude of drug-nutrient interactions may be more pronounced in the young infant. An
advanced understanding of developmental changes in intestinal transporter activity
will facilitate understanding of the potential for drug-drug and drug-nutrient interac-
tions in young children.

Extraoral Absorption
Despite conventional preferences to deliver drugs orally, nonoral routes of administra-
tion may be preferred in some settings. As with peroral administration, the absorption
of extraorally administered drugs is also subject to developmental variation. The
 Pediatric Pharmacokinetics 1005

absorption of rectally administered drugs depends in part on drug dissolution profiles

within the lower intestinal tract. Rectal formulations with delayed release characteris-
tics (ie, erythromycin, acetaminophen) may experience decreased residence times in
young infants owing to an increase in the number of high-amplitude pulsatile contrac-
tions of the lower intestine.27 Preterm neonates have enhanced rectal acetaminophen
bioavailability, possibly caused by reductions in presystemic metabolism, intestinal
motility, or temperature instability.28
Although infrequently used, percutaneous administration can be an efficient means
of delivering drugs to children. The increased systemic exposure experienced by chil-
dren is a product of developmental differences in the neonate and young infant that
result in enhanced percutaneous absorption, namely an increased body surface
area/mass ratio, higher rates of tissue perfusion, and a higher degree of skin hydra-
tion.29,30 These differences can increase a child’s risk of toxicity to topically applied
agents even when systemic exposure is not the goal of treatment. Unintended conse-
quences of topical agents have been shown for numerous agents, such as antihista-
mines, steroids, sulfadiazine, talcum powder, and laundry detergent.31
In addition, absorption following intramuscular (IM) injection is considered. Although
IM absorption of some drugs in children is reported as erratic, others are efficiently
absorbed by this route, which may be explained by increases in capillary density
(25%–50%) experienced by the young infant to assist with the metabolic demands
of growth and development.32 Peak plasma concentrations for some drugs (eg, ceph-
alosporins, aminoglycosides) are consequently significantly higher in neonates
compared with young children, presumably reflecting a change in the rate of absorp-
tion from the site of administration.33,34

DISTRIBUTION

Once absorbed into the systemic circulation, the extent to which a drug penetrates
extravascular tissues is described by the drug’s volume of distribution (Vd). The under-
lying determinants of drug distribution include the physiologic characteristics of the
tissue and the physicochemical and transport properties of the drug. Thus, physio-
logic changes observed throughout development can have a sizable impact on the
distribution properties of a drug.
One of the more prominent changes that influence drug distribution is the fluid
composition of the body. Water comprises approximately 80% of a newborn infant’s
body weight, with fractional decreases over the first 4 months of life to adult levels
(approximately 60%) (Fig. 2A).35 Hydrophilic drugs that are mainly restricted to the
aqueous fluid compartments (eg, gentamicin, linezolid) consequently have a larger
apparent Vd and decreased plasma concentrations in the young infants.36,37 In
conjunction with developmental changes in drug clearance, these children can expe-
rience circulating concentrations that fail to adequately meet pharmacodynamic
criteria if dose and dosing interval are not adjusted for age.37–39
As opposed to total body water, total body fat stores are reduced in infants and
approach adult values in the first years of life, with age-dependent fluctuations
throughout childhood (see Fig. 2B). Based on these changes, it theoretically could
be expected that lipophilic drugs would show a lower Vd in infants and young children;
however, this is largely not observed, because these drugs tend to freely associate
with cellular components in tissues other than adipose. The failure to observe a lower
Vd for lipophilic agents in young children may also indicate that additional tissue reten-
tion mechanisms compensate for the changes in body composition. A variety of reten-
tion mechanisms can facilitate the partitioning and accumulation of drugs in tissue.40
1006 Funk et al

Fig. 2. (A) Body water composition as a percentage of body weight in neonates, infants, young
children, and adults. (B) Age-dependent changes in tissue mass relative to total body weight.

For example, a subset of drugs with extremely large Vd accumulate in tissues through
their affinity for acidic subcellular compartments (ie, lysosomes), which are enriched in
the liver, lung, heart, brain, and kidneys.41,42 Thus, age-dependent changes in the
mass of these organs relative to total body mass would result in Vd differences with
 Pediatric Pharmacokinetics 1007

age (see Fig. 2B), particularly when blood flow/volume to these tissues is comparable
with or greater than that of adults.43 Although speculative, these changes in fractional
organ mass may contribute to changes in the Vd, and future studies addressing the
impact of development on tissue retention mechanisms are needed to more thor-
oughly evaluate their relevance to pediatric pharmacotherapy.
A drug must exist in its free, unbound form to distribute out of the central compart-
ment and into extravascular tissues. Therefore, the apparent Vd of a drug depends not
only on its ability to enter and accumulate in tissue but also on the free fraction of the
circulating drug. Protein binding depends on the quantity of circulating plasma
proteins (eg, a-1-acid glycoprotein [AAG] and albumin), the drug’s binding affinity
for these proteins, and the presence of endogenous or exogenous substances that
compete for binding sites, including free fatty acids, bilirubin, and other drugs.44–46
Development influences each of these factors, with neonates and young infants expe-
riencing reduced concentration of albumin and AAG, protein isoforms for which drugs
have a reduced affinity, and increased circulating concentrations of ligands that can
displace drugs from their binding sites.47 Compared with older children and adults,
young infants experience increased free fractions, and thus increased Vd, of many
drugs (eg, barbiturates, opioid analgesics).48,49 The clinical importance of develop-
mental changes in the fractional protein binding of drugs ultimately depends on the
therapeutic agent under consideration and its therapeutic index.
Although limited data are available describing the ontogeny of transmembrane
proteins responsible for the cellular uptake and efflux of drugs, there is strong biologic
evidence to support the assertion of a developmental expression profile. The endog-
enous substrates for these transport proteins include a variety of substances that are
crucial to normal human growth and development (eg, metals, electrolytes, amino
acids, nucleotides, lipids, carbohydrates, steroids). Realizing that these substrates
are used by different tissues to different extents throughout development, adaptive
mechanisms that control transporter expression and activity are likely involved. To
date, only limited data from postmortem brain tissue are available, suggesting that
P-gp, MRP1 (multidrug resistance protein 1), and BCRP (breast cancer resistance
protein) all show distinct anatomic and cellular expression patterns that are develop-
mentally dependent.50 Such differences may explain changes in the central nervous
system (CNS) penetration of drugs that are substrates for these transport proteins;
however, other studies suggest that changes in pore density and regional blood
flow may account for age-dependent differences in CNS drug penetration.
METABOLISM

In addition to the liver functioning in a variety of life-sustaining synthetic and digestive

processes, it also serves as the predominant organ of metabolism for exogenously
administered drugs. Hepatic clearance pathways are usually divided into phase I
(eg, oxidation, reduction, hydrolysis) and phase II (eg, covalent conjugation) reactions.
The DMEs responsible for drug bioconversion are found in multiple tissues other than
the liver; however, these extrahepatic sites (with the exception of the intestine) are of
minimal significance in overall drug clearance and this article only discusses the liver.
As alluded to earlier, an understanding of the ontogeny of DMEs helps to appreciate
the potential for drug-drug, drug-nutrient, and drug-gene interactions in children.
Phase I Metabolism
Phase I drug metabolism is typically performed by a group of mixed-function oxidases
referred to as the cytochromes P450 (CYPs). These enzymes are highly expressed in
the liver; CYP3A4 being the most clinically relevant followed by CYP2D6 > CYP2C >
1008 Funk et al

CYP2E1 > CYP1A2. Although the fetus expresses a high level of CYP3A7, humans
undergo an isoform switch shortly after birth and CYP3A7 rapidly decreases coinci-
dent with a steady increase in CYP3A4 expression and activity through the first year
of life (Fig. 3A).51,52 The clinical implications of this profile can be shown for numerous
CYP3A substrates (eg, sildenafil, cisapride) that show marked reductions in half-life
during infancy.15,53,54
In contrast with CYP3A4, CYP2D6 reaches adult activity levels by 2 weeks of life.55
For this enzyme, genetic variations seem to have a greater impact on activity than
does development. Within the CYP2C family, the 2 predominant isoforms display
distinct developmental patterns. CYP2C9 expression and activity in human liver
microsomes suggest that, in the early postnatal period (0–5 months), enzyme activity
and expression are similar to those of older children (5 months–18 years). In contrast,
CYP2C19 expression seems to increase over the first 6 months of life, with a corre-
sponding increase in substrate-specific activity.56 Interestingly, PK data for the
CYP2C9 substrate phenytoin reveals a terminal half-life that decreases from 20 hours
at birth to 8 hours at 2 weeks of life.57,58 Further, intravenous PK data for the CYP2C19
substrate omeprazole have been found to have high clearance rates in the young
infant that normalizes in the first 5 years of life.59,60 The discrepancy between the
data observed in vitro and pediatric PK data highlights the complexity of predicting
in vivo processes in the growing child based on in vitro data. This assertion is

Fig. 3. (A) Developmental changes in the activities of hepatic CYP3A4 and CYP3A7. (B)
Sulfate and glucuronide conjugates of acetaminophen as a percent of total dose in
newborns, children and adults. DHEA, dehydroepiandrosterone.
 Pediatric Pharmacokinetics 1009

reinforced by the finding that CYP2C9 and VKORC1 genotypes explain less of the vari-
ability in warfarin dosing for children than they do in adults.61
Although not responsible for the metabolism of a large number of marketed drugs,
CYP2E1 is important in the metabolism of a variety of anesthetic agents and has been
found to be differentially expressed throughout development. Protein and activity
levels are negligible in the prenatal period but gradually increase to within 80% of adult
levels by the first year of life.62 CYP1A2 similarly shows negligible levels of activity in
the prenatal period and levels in the neonate are 4% to 5% of those found in adults.
CYP1A2 activity steadily increases with age to 10% to 15%, 20% to 25%, and 50%
to 55% of adult values at 1 to 3 months, 3 to 12 months, and 1 to 9 years of age,
respectively.63

Phase II Metabolism
The conjugation reactions performed by phase II DMEs serve to increase the water
solubility of the drug molecule, thereby facilitating excretion. Multiple gene families,
each with multiple isoforms, are involved in these reactions, including uridine 50 -
diphosphoglucuronosyltransferases (UGTs), GSTs, N-acetyltransferases (NATs), and
sulfotransferases (SULTs).
UGT1A1, involved in the metabolism of acetaminophen, ibuprofen, and warfarin, is
absent in the fetal liver but measurable immediately after birth and expressed at adult
levels by 3 to 6 months of life.64 Transcript levels of UGT1A9, involved in the metab-
olism of ethinyl estradiol, ibuprofen, and acetaminophen, are approximately 44% of
those seen in adults at 6 months of life and 64% of the adult values by 2 years of
age.65 Using morphine clearance as a surrogate, the activity of UGT2B7 seems to
be low in premature neonates but increases to levels greater than those observed in
adults in the first year of life.66
SULTs are involved in the biosynthesis and metabolism of multiple endogenous
biochemicals including steroid hormones, catecholamines, and thyroid hormone.
SULT1A1 seems to be expressed in the fetal liver at levels comparable with those
of children and adolescents. In contrast, SULT2A1 shows a significant increase during
the first 3 months of life when activity levels comparable with those of adults are
achieved.67 In addition, data on GSTs A1 and A2 (DMEs that facilitate the conjugation
of glutathione to the electrophilic centers of endogenous and exogenous substrates)
reveal that both enzymes are present in the fetal liver but that adult expression levels
are not achieved until 1 to 2 years of life.68
Compensatory metabolic pathways are in place for many of the phase I and phase II
DMEs that are developmentally dependent. For some drugs, the total function of all
relevant compensatory pathways may result in no change in the overall clearance of
the drug as a function of age. For other drugs, the compensatory pathways may not
be as efficient, resulting in age-dependent reductions in total body clearance. For
example, acetaminophen is primarily metabolized via UGT1A6 and SULT1A1, with
adults predominantly using the former pathway and newborns the latter (see
Fig. 3B).69 Despite compensatory sulfation in young infants, these patients still exhibit
an increased half-life compared with children and adolescents.70 Thus, the clinical re-
levance of ontogenic variation in DMEs depends, in part, on the presence of compen-
satory metabolic pathways, the therapeutic index of the drug, and the nature of the
metabolites that are formed.
The ontogeny of biologic pathways involved in the metabolism of large-molecular-
weight therapeutic agents also needs to be discussed; however, very limited data
exist on this topic. Among the limited existing data is the example of antihemophilic
factors. Factor VIII, a protein involved in the clotting cascade, shows a shorter
1010 Funk et al

half-life in infants and young children 1 to 6 years of age (9.2 hours) compared with in
adolescents and adults 10 to 65 years of age (12.2 hours).71 PK studies on insulin,
growth hormone, and erythropoietin all seem to suggest age-dependent changes in
clearance as well.72–77 With the increase in the number of biologic agents being
brought to the market and their increased use in children, it will be important to char-
acterize the disposition pathways of these proteins and their ontogeny.

EXCRETION

In addition to maintaining electrolyte and fluid homeostasis, the kidney is the predom-
inant organ responsible for the excretion of drugs and their metabolites. Structural and
functional maturation of the kidney occurs throughout childhood and these changes
are well described elsewhere.78–80 Although glomerular filtration rate (GFR) and renal
tubular secretion are low in the newborn, they reach and exceed adult levels within the
first few years of life (Fig. 4A).81 Such changes contribute to reduced clearance of
renally eliminated drugs in the neonate and increased clearance of renally excreted
drugs in young children.82 For example, pharmacokinetic studies of vancomycin indi-
cate that total body clearance averages 1.14 mL/min/kg in neonates (<1 month of

Fig. 4. (A) Age-dependent changes in GFR and p-aminohippurate (PAH) clearance. (B) Post-
natal and developmental changes in renal filtration capacity in preterm and term neonates.
 Pediatric Pharmacokinetics 1011

age), 1.91 mL/min/kg in infants (1–12 months of age), and 3.17 mL/min/kg in children
older than 1 year of age (average age of 5.8 years), compared with 0.92 mL/min/kg in
adults with normal renal function.83,84 These changes in renal clearance often neces-
sitate significant dose modifications for renally cleared drugs.
Compared with the full-term neonate, GFR is significantly reduced in the premature
neonate after birth (see Fig. 4B).80 Despite a notable increase in the first 2 weeks of life,
GFR in premature neonates remains significantly suppressed compared with full-term
neonates, suggesting differences in the maturation of the filtration process in these 2
populations. These observed differences in renal architecture and perfusion with age,
both gestational and postnatal, result in clear developmental PK profiles for drugs that
are passively and actively cleared by the kidney. For example, fluconazole’s pro-
tracted half-life in premature infants (88 hours vs 19.5–25 hours in full-term infants)
directly affects the dosing recommendations for this antifungal.85
In contrast with passive filtration, little is known about renal secretory pathways in
children, with the exception of the proteins involved in the tubular secretion of p-ami-
nohippurate (PAH).80 Among the numerous remaining transporters involved in drug
translocation, developmental expression profiles for these proteins have yet to be
defined in humans. Studies on transporter expression in rats and mice have shown
a clear age dependence that may suggest what will be found for humans.86–90 In addi-
tion, excretion cannot be reviewed without addressing biliary clearance, an often over-
looked, but significant, contributor to drug disposition. The first few weeks of life seem
to be accompanied by reduced expression of the hepatic transport proteins that facil-
itate biliary drug clearance.91 Reduced biliary drug excretion in neonates corresponds
with increased fractional urinary excretion of several drugs (eg, ceftriaxone, cefoper-
azone).92,93 Depending on the transport proteins involved and the ratio of biliary excre-
tion to total drug clearance, age-dependent changes in biliary secretion may or may
not cause clinically significant changes in drug clearance.

SUMMARY

For special populations in which there are only limited data to guide drug dosing, it is
crucial for the clinician to understand how underlying physiologic changes within the
population can affect drug disposition. In pediatrics, an understanding of the underlying
physiologic changes can be garnered through a working knowledge of developmental
biology. Through an understanding of the physiologic processes that dictate the dispo-
sition properties of a drug, the pediatric clinician can arrive at rational recommendations
when selecting and optimizing drug therapy. As long as deficits continue to exist in the
understanding of the physiologic processes involved in drug disposition, it will not be
possible to fully appreciate the impact of ontogeny on these processes. In many cases,
observations made in clinical PK studies will lay the foundation that ultimately expands
understanding of the role of developmental changes on drug disposition.

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