Pediatrics in Review Vol. 19 No.

12 December 1998 423

ARTICLE
Definition
Pharmacology in its broader sense
refers to the history, chemicophysi-
cal properties, source, biochemical
and physiological effects, disposi-
tion, mechanisms of action, and
therapeutic and nontherapeutic uses
of drugs. This definition obviously
is beyond the interest of most clini-
cians. The demand for a clinically
oriented discipline has led to the
development of clinical pharma-
cology, which focuses on the effects
of drugs in humans.
The subdiscipline of pediatric
clinical pharmacology presents
difficult challenges. Rapid and
significant age-related physiologic
changes, especially during the
first year of life, dictate a dynamic
yet cautious therapeutic approach.
Furthermore, despite a significant
increase in the knowledge of drug
disposition in infants and children
over the past few years, pharma-
cokinetic/pharmacodynamic inter-
actions remain poorly understood.
Finally, many obstacles prevent
rational and timely accumulation
of important data about drug han-
dling and response in children.
Only recently have pediatric clini-
cal pharmacology studies been
expected by the United States Food
and Drug Administration (FDA) as
an integral part of regulatory review
for all agents used in children.
Hopefully this will lead toward
evidence-based pharmacotherapy
in the pediatric population.
Epidemiology
According to one report, an average
of 0.9 medication per patient-contact
is prescribed in pediatric practice
compared with 1.1 drugs per
patient-contact for all the disci-
plines together. By their first 5 years
of life, 95% of children have been
prescribed medications, with an
average of 8.5 courses of prescrip-
tions and 5.5 different medications.
Within this 5-year period, the great-
est number of prescriptions is given
to children between 7 and 12 months
of age. These data, together with the
limited clinical drug trials that have
been conduced in infants and chil-
dren, suggest the need for a more
evidence-based approach similar to
the pharmacotherapy employed in
other age groups.
Pharmacokinetic Principles
in Neonates and Infants and
Their Clinical Relevance
Neonates and infants represent an
unstable pharmacokinetic condition.
Special attention must be paid to
pharmacokinetic variables as rapid
and significant age-related changes
in drug absorption, distribution,
and clearance occur in the first
few months of life.
DRUG ABSORPTION
Drug absorption in infants and
children follows the same general
principles as in adults, but because
relatively more sites of drug admin-
istration are used in neonates, spe-
cial considerations must be paid to
the different determinants affecting
drug absorption from each site.
Absorption from the Gastrointestinal
(GI) Tract
Diminished intestinal motility and
delayed gastric emptying in neo-
nates and infants result in a longer
period of time for a drug to reach
similar plasma concentrations in
infants as in older children after
oral administration. Oral absorption
of acetaminophen, phenobarbital,
and phenytoin, reflected in part by
bioavailability, has been shown to
be lower in infants than in older
children and adults (Table 1).
Different flora colonize the sterile
fetal intestine, depending on whether
the newborn is breastfed or formula-
fed. The change in bacterial flora
during the newborn period affects
the hydrolysis of drug conjugates
that are excreted in bile. Absorption
Clinical Pharmacology and Therapeutic Drug
Monitoring in Neonates and Children
Ronen Loebstein, MD* and Gideon Koren, MD*
IMPORTANT POINTS
1. Neonates and children exhibit unstable pharmacokinetics, and knowl-
edge of age-related changes in drug absorption, distribution, and
clearance is essential to optimize drug efficacy and avoid toxicity.
2. Measurement of drug concentrations at times of the expected peak or
trough is crucial for accurate interpretation and subsequent dosing;
lack of knowledge of the time of drug delivery to the patient or
random sampling will result in useless therapeutic drug monitoring.
3. Administration of drugs that inhibit hepatic drug metabolism (such as
cimetidine, erythromycin, ciprofloxacin, or omeprazole) concomitantly
with drugs metabolized by the liver that have a narrow therapeutic
range may lead to increased plasma concentrations and, therefore,
toxicity.
4. Explaining the nature of the illness and providing precise instructions
about treatment, including the names and purposes of the drug(s)
prescribed and specific instructions about dosage, have been
demonstrated to improve compliance.
5. Although most drugs are excreted into human milk by passive
diffusion, the amount ingested by the infant rarely is sufficient to
attain therapeutic concentrations or cause adverse effects.
*Division of Clinical Pharmacology and
Toxicology, Department of Pediatrics and
Population Health Sciences, Research
Institute, The Hospital for Sick Children,
University of Toronto, Toronto, Ontario,
Canada.

424 Pediatrics in Review Vol. 19 No. 12 December 1998
of vitamin K and other lipid-soluble
vitamins also is influenced by the
development of intestinal flora.
Disease conditions such as diar-
rhea, giardiasis, cystic fibrosis, and
celiac disease might interfere with
drug absorption from the GI tract.
Rectal Administration of Drugs
Rectal drug administration may be
useful in conditions such as nausea
and vomiting and status epilepticus,
for induction of anesthesia, and for
administration of drugs that have a
large first-pass effect (blood supplies
to the anus and lower rectum drain
directly into the inferior vena cava).
Solutions of diazepam have been
demonstrated to be well absorbed
from the rectum compared with
suppositories, for which absorption
is erratic and incomplete. In light
of its poor absorption from intra-
muscular injection sites, rectal
administration of diazepam solutions
offers effective anticonvulsive and
sedative therapy, especially because
diazepam bioavailability has been
shown to be higher after rectal than
oral administration.
In addition to benzodiazepines,
barbiturates have been administered
rectally to children with great suc-
cess. Rectal diazepam has been
used effectively in the treatment
of febrile seizures. Similarly, rec-
tally administered midazolam and
atropine for other indications were
clinically more effective than intra-
muscular administration.
Absorption from Intramuscular
Injection Sites
Local and drug-related factors are
the most important determinants
affecting drug absorption after
intramuscular injection. Blood
supply and flow to and from the
injected muscle are the most im-
portant local factors. Clinical con-
ditions such as low cardiac output,
respiratory distress syndrome, and
other circulatory disturbances
may compromise blood supply to
the muscles severely, leading to
decreased absorption from the
injection site. The degree of muscu-
lar activity affects primarily the rate
of drug absorption from intramuscu-
lar sites. Immobile infants demon-
strate slower absorption rates from
intramuscular injection sites; exer-
cise may enhance drug absorption,
as has been demonstrated for insulin
and exercise-induced hypoglycemia.
Phenytoin provides a classic
example of drug-related factors
affecting absorption from intramus-
cular injection sites. This drugs pK
is 9.2, and the acid form is insoluble
in water. Because the muscle envi-
ronment is more acidic than blood,
the sodium salt of phenytoin is con-
verted into the acid form, which
precipitates at the site of injection.
This results in slow and erratic
absorption of phenytoin from
intramuscular sites.
More rapid absorption following
intramuscular administration has
been demonstrated for benzathine
penicillin and clindamycin in the
pediatric age group compared
with adults.
DRUG DISTRIBUTION AND
PROTEIN BINDING
Drug distribution and protein bind-
ing in neonates and children are
dictated by changes in body compo-
sition that occur with development.
The total body water compartment
is larger among preterm neonates
(85% of total body weight) com-
pared with term neonates (70% to
75%) and adults (50% to 60%).
Similarly, the extracellular water
compartment is 40% of body weight
in the neonate compared with 20%
in the adult. These data are clini-
cally relevant because many drugs,
especially water-soluble ones (eg,
aminoglycosides), are distributed
throughout the extracellular water
compartment. Therefore, the volume
of the extracellular water compart-
ment determines drug concentration
at the receptor site. Conversely, total
body fat in preterm infants is 1% of
total body weight compared with
15% in term neonates. This affects
lipid-soluble drugs such as digoxin,
which may accumulate in smaller
amounts in immature infants.
Another determinant of drug
distribution is protein binding.
Generally, neonates, especially
preterm neonates, are at risk of
altered drug-protein interaction.
Decreased plasma concentrations
of total protein and albumin in
newborns and infants lead to
decreased drug-protein binding.
In vitro studies comparing free
drug concentrations in cord blood
and adult plasma have demonstrated
significantly higher cord/adult free
drug ratios for salicylates, sulfon-
amides, morphine, phenobarbital,
and phenytoin. Because the free
drug exerts the pharmacologic drug
effect, the increased free drug con-
centrations in neonates may result in
greater drug effect or even toxicity
despite normal total (bound plus
unbound) drug concentrations.
Increased concentrations of free
fatty acids and unconjugated biliru-
bin in the newborn also affect drug
protein binding. Both free fatty
acids and unconjugated bilirubin
have high affinity for albumin,
which can result in competition
and even displacement of drugs
from albumin binding sites.
Differences in the distribution
of different agents into the central
nervous system are clinically im-
portant in antimicrobial therapy for
meningitis. The relatively tighter
junctions in the brain endothelial
capillaries and the close approxima-
tion of the glial connective tissue
to the capillary endothelium limit
the distribution of drugs to brain
tissue. This is especially relevant for
water-soluble antibiotics (eg, amino-
glycosides), which are less likely to
cross the blood-brain barrier.
CLEARANCE
Hepatic Drug Metabolism
Although the major organ of drug
metabolism is the liver, many other
organs, including the lungs, GI tract,
PHARMACOLOGY
Drug Monitoring
TABLE 1.
Oral Drug Absorption
(Bioavailability) of Selected
Drugs in Neonates Compared
with Older Children
ORAL
DRUG ABSORPTION
Acetaminophen Decreased
Ampicillin Increased
Diazepam No change
Digoxin No change
Pencillin G Increased
Phenobarbital Decreased
Phenytoin Decreased
Sulfonamides No change

Pediatrics in Review Vol. 19 No. 12 December 1998 425
or blood, are capable of metaboliz-
ing drugs. Drug metabolism can
result in either generation of weaker
or inactive metabolites or transfor-
mation of a parent compound or
prodrug into the active compound
(theophylline to caffeine, codeine to
morphine) or an even more active
metabolite. Drug metabolism is
categorized in two major steps:
phase I reactions in which a mole-
cule is biotransformed into a more
water-soluble metabolite and phase
II reactions in which a drug or its
metabolite is conjugated with en-
dogenous molecules.
Generally, phase I reactions
(oxidation, reduction, methylation)
reach maximal maturity by 6 months
of age. Age-related changes in drug
metabolism have been demonstrated
for theophylline. In neonates, only
10% of theophylline is methylated
to caffeine, with 50% of the drug
excreted unchanged in the urine.
With maturation of the hydroxyl-
ation and acetylation of hepatic
enzymes, the rate of theophylline
clearance increases, resulting in
the short half-life demonstrated
in infants and children (3 to 5 h)
compared with adults (8 h).
Hepatic phase II reactions (gluco-
ronidation, sulfation, acetylation) are
substantially lower (50% to 70% of
adult values) in early neonatal life.
Glucuronide formation reaches its
full maturity (adult values) between
the third and fourth years of life.
The decreased ability of neonates
to metabolize drugs results in pro-
longed elimination half-lives. Drug
doses and dosing schedules that do
not take into account these changes
predispose neonates to adverse
drug reactions and even to toxicity
from overdose.
Drug Excretion (Table 2)
Renal function demonstrates an age-
dependent increase in functional
capacity. The glomerular filtration
rate (GFR) in neonates is 30% to
40% of the adult value. By the end
of the first week of life, both the
GFR and renal plasma flow have
increased by 50%. By the end of the
third week, GFR is usually 50% to
60% of the adult value and by 12
months, it reaches the adult value.
The clinical relevance of these
changes is apparent with renally
eliminated agents such as amino-
glycosides, penicillins, and digoxin.
For example, the dosage of genta-
micin for a neonate younger than
7 days of age is 5 mg/kg per day
divided into two doses at 12-hour
intervals. This dosage changes to
7.5 mg/kg per day divided into three
doses at 8-hour intervals in children
older than 7 days. Similarly, renal
clearance of digoxin has been
demonstrated to increase from
33 mL/min/1.73 m
2
in neonates
to 98 and 144 mL/min/1.73 m
2
at
3 months and 1.5 years, respectively.
Because certain disease states
may alter the normal maturation
process of renal function, dose
adjustments that usually are made
according to the predicted rate of
renal function maturation during
the first weeks of life may not be
appropriate.
Drug Interactions
Clinically significant drug interac-
tions can be defined as clinically
measurable modifications in either
magnitude or duration of action of
one drug caused by prior or con-
comitant administration of another
substance. Some drug interactions
can be desirable, such as seen with
the treatment of hypertension by
using multiple drugs with different
mechanisms of action. Other interac-
tions can be adverse. It is estimated
that serious, life-threatening adverse
drug reactions occur in 3% of hospi-
talized patients, with 7% of these
caused by drug interactions. Mecha-
nisms of drug interactions can be
classified as pharmacokinetic and
pharmacodynamic.
INTERACTIONS AFFECTING
ORAL BIOAVAILABILITY
Drug interactions in the GI tract
can decrease the oral bioavailability
of the index drug. For example,
tetracyclines can chelate calcium,
magnesium, or iron, leading to
decreased absorption of the cation-
tetracycline complex. Drugs that
damage the intestinal absorptive
surface, such as oral neomycin or
antineoplastic agents, may lead to
decreased absorption of otherwise
well-absorbed drugs.
Gastric emptying can be phar-
macologically enhanced (metoclo-
pramide, domperidone) or delayed
(morphine, anticholinergics, ant-
acids), which affects the rate
rather than the extent of absorption.
This may be clinically relevant
when a rapid onset of drug effect
is desired (eg, pain relief, sedation,
sepsis). Finally, for drugs that
have an extensive first-pass effect
(ie, those that are extracted or
metabolized during transit across
the intestinal epithelium or during
the first pass through the liver), such
as beta-blockers, calcium channel
blockers, tricyclic antidepressants,
and morphine, the primary factor
affecting clearance is hepatic blood
flow. Therefore, coadministration of
drugs that decrease hepatic blood
flow such as cimetidine would be
expected to raise the steady-state
PHARMACOLOGY
Drug Monitoring
TABLE 2. Changes in Elimination Half-life (hours)
During Development
NEWBORN INFANT
DRUG (0 TO 28 d) (1 TO 24 mo) CHILD ADULT
Acetaminophen 4.9 4.5 3.6
Amikacin 5.0 to 6.5 1.6 2.3
Amoxicillin 3.7 0.9 to 1.9 0.6 to 1.5
Cefuroxime 5.5 3.5 1.2 1.5
Diazepam 30 10 25 30
Digoxin 18 to 33 37 30 to 50
Gentamicin 4.0 2.6 1.2 2 to 3
Theophylline 30 6.9 3.4 8.1
Vancomycin 4.1 to 9.1 2.2 to 2.4 5 to 6

426 Pediatrics in Review Vol. 19 No. 12 December 1998
concentration of the previously men-
tioned agents.
PROTEIN BINDING
DRUG INTERACTIONS
Protein is bound primarily to albu-
min and alpha2-glycoprotein. The
serum concentration of a measured
drug usually refers to the total drug
concentration in the plasma (free
plus protein bound), although only
the free drug exerts the pharmaco-
logic effect. Drugs that are highly
bound to proteins are subject to
displacement by other drugs that
have high affinity for the same
protein binding sites. This may
result in a transient increase in the
free concentrations of the index
drug, followed by redistribution
and increased clearance, creating
a new equilibrium of both drugs.
This phenomenon will result in
clinically significant effects in
cases in which the index drug has
a small volume of distribution, a
narrow therapeutic window, and
rapid onset of action in relation
to its plasma concentration.
DRUG INTERACTIONS AFFECT-
ING BIOTRANSFORMATION
Many of the prescribed drugs in the
pediatric population may inhibit or
enhance the metabolism of other
drugs. The significance of this inter-
action is dictated by the magnitude
of the decrease or increase in clear-
ance of the index drug. Generally,
modifications in the magnitude of
hepatic drug metabolism caused by
drug-drug interactions are difficult
to predict because most drugs are
metabolized by several different
pathways, and the quantitative
fraction of each pathway is hard
to evaluate.
Most inhibitors of hepatic drug
metabolism bind to an essential part
of the enzyme system, resulting in
a functionally impaired or inactive
enzyme that cannot oxidize, reduce,
or hydrolyze medications. The most
useful agents that have inhibitory
effects on hepatic drug metabolism
prescribed for the pediatric age
group are cimetidine, erythromycin,
ciprofloxacin, and omeprazole.
Coadministration of these agents
with a medication that has a narrow
therapeutic range, such as theophyl-
line, may result in increased plasma
concentration and even toxicity of
the theophylline.
Enzyme induction, on the other
hand, can enhance the clearance of
index drugs, which can lead to
decreased or even loss of efficacy.
Rifampin, a well-known inducer
of hepatic metabolism, has been
implicated as a potential cause of
graft rejection via increased clear-
ance of cyclosporine and predni-
sone. It also has been claimed to
be the cause of oral contraceptives
failing because of their increased
metabolism. Phenytoin, another
inducer of hepatic biotransforma-
tion, has been shown to induce
withdrawal symptoms in patients
receiving methadone chronically.
The ability of phenobarbital to
induce the oxidizing enzyme sys-
tem found in hepatic endoplasmic
reticulum may enhance the hepatic
metabolism of any drug that under-
goes metabolism by this system.
Phenobarbital-induced effects on
the metabolism of drugs from a vari-
ety of classes have been reported,
including analgesics (acetamino-
phen), antibacterials (chlorampheni-
col, doxycycline, metronidazole),
anticoagulants (warfarin), beta-
blockers (propranolol), cortico-
steroids, and opioid analgesics.
If an induction interaction is
established, the dose of the index
drug should be increased. If the
inducing drug is discontinued, the
index drug dose should be decreased
to avoid toxicity.
DRUG INTERACTIONS DUE TO
ALTERED RENAL FUNCTION
Drugs excreted entirely by glomer-
ular filtration are unlikely to be
affected by other drugs. However,
clearance of drugs that are actively
transformed into the tubular lumen
can be inhibited significantly by
other drugs. Methotrexate toxicity
may be induced by inhibition of
its tubular secretion by salicylates.
Renal clearance of lithium is re-
duced significantly in the presence
of thiazides, and a low effective
circulating volume combined with
increased sodium reabsorption
increases lithium reabsorption.
Drug interactions may have ad-
vantages. For example, probenecid
enhances the tubular secretion of
penicillin.
The pediatrician should try to
decrease the possible risk of drug
interactions by being cognizant of
the potential in high-risk clinical
settings. Drugs that have low toxic/
therapeutic ratios and a steep dose-
response relationship represent a
major risk. Clinically relevant exam-
ples of such drugs include warfarin,
digoxin, lithium, theophylline, and
aminoglycosides. Patients at risk
for drug interactions include those
receiving polypharmacy (the risk of
drug interaction increases with the
number of drugs used), critically ill
patients, and drug abusers.
Drug Use During Lactation
The relevance of drug use during
lactation is highlighted by the pat-
tern of breastfeeding over the past
several decades. In the United
States, the proportion of women
breastfeeding their babies was
estimated at 60% in the late 1980s
compared with 30% in the 1950s.
Most drugs are excreted into
human milk by passive diffusion,
making the drug concentration in
milk directly proportional to the
concentration in maternal plasma.
Because human milk is slightly
more acidic than plasma, drugs that
typically pass into milk are weak
bases, lipid-soluble, and poorly
bound to proteins. The milk:plasma
(M:P) ratio, which compares drug
concentrations in milk with that
in maternal plasma, serves as an
index of the extent of drug excre-
tion in the milk (Table 3). However,
to determine infant exposure to
drugs in human milk, the infants
clearance of the drug also must
be considered.
PHARMACOLOGY
Drug Monitoring
The most useful drugs that have inhibitory effects on
hepatic drug metabolism prescribed for the pediatric age group
are cimetidine, erythromycin, ciprofloxacin, and omeprazole.

Pediatrics in Review Vol. 19 No. 12 December 1998 427
The following general principles
can guide management of cases of
drug exposure in a breastfed infant:
1. The human milk drug concentra-
tion usually does not exceed the
maternal plasma concentration.
2. Even when the M:P ratio for
a given drug approaches or
exceeds 1.0, the amount of drug
ingested by the infant rarely is
sufficient to attain therapeutic
concentrations.
3. Short exposure to a drug is usu-
ally of less concern than a drug
given for a long period of time.
4. The amount of drug ingested
can be minimized by feeding
the infant just before or at the
time of maternal administration.
The American Academy of
Pediatrics lists the following drugs
as being contraindicated during
breastfeeding:
Bromocriptine and ergotamine
because of their activity in sup-
pressing prolactin.
All neoplastic agents because of
their potential ability to induce
myelosuppression in the neonate
and concerns about carcinogenic-
ity later in life.
In addition, temporary cessation
of breastfeeding is advised in the
presence of some radioactive com-
pounds.
Lithium enters human milk in
concentrations equal to those in
maternal serum. Clearance of this
agent depends almost entirely upon
renal elimination, and women
treated with lithium may expose
their babies to relatively large
amounts of the drug. Amiodarone
has been demonstrated to be present
in large amounts in human milk.
During such therapy, infant thy-
roid function should be monitored
because this drug can cause hyper-
or hypothyroidism.
Propylthiouracil is the drug of
choice for maternal hyperthyroidism
during lactation because the amount
that the infant would ingest is esti-
mated to be less than 1% of the
mothers dose on a bodyweight
basis compared with up to 12%
for methimazole. Despite such low
levels of exposure, a potential risk
of thyroid suppression in the infant
remains, prompting the recommen-
dation of clinical and laboratory
evaluation of thyroid stimulating
hormone.
Carbamazepine, phenytoin, and
valproic acid are considered com-
patible with breastfeeding because
the exposure levels of the infant to
these drugs is less than 10% of the
expected exposure if the drug were
administered directly. Phenobarbital,
on the other hand, can result in
exposure levels of 100% primarily
because of low clearance of this
agent in neonates. Clinical and drug
concentration monitoring in human
milk and in the plasma of the infant
is recommended. Another considera-
tion is the ability of phenobarbital
to induce fetal hepatic enzymes,
which can result in the neonate
metabolizing certain drugs more
than expected, leading to less thera-
peutic effects and lower plasma
drug concentrations following an
unadjusted neonatal dose.
Compliance
The incidence of noncompliance in
the pediatric age group is as signif-
icant as in adult medicine. About
21% of adolescents are reported
noncompliant with anticonvulsant
therapy, 28% of asthmatic children
are noncompliant with theophylline,
and 30% to 40% of thalassemia
major patients are noncompliant
with nightly subcutaneous infusions
of desferrioxamine.
Reasons for noncompliance range
from simple forgetfulness to the ex-
treme of neglect, and they reflect the
patients or the parents perception
of the seriousness of the illness and
the degree of effort required by the
recommended treatment. The clini-
cians role in improving compliance
is extremely important. Taking time
to explain the nature of the illness,
providing precise instructions for
treatment (including the names and
purposes of the drug or drugs pre-
scribed), and giving specific instruc-
tions about dosage have been shown
to improve compliance.
Objective methods to assess
compliance have not been applied
widely in the pediatric population.
Patients or parents self-reports,
return tablet counts, and random
measurement of serum concentra-
tions may help disclose noncompli-
ance, although the reliability of
these methods is limited. The use
of computerized pill containers
that record each lid opening has
been shown to be very effective
in measuring compliance.
Therapeutic Drug
Monitoring (TDM)
TDM is defined as the measure-
ment of drug concentrations and
the use of pharmacokinetic princi-
ples to individualize drug dosing in
an attempt to maximize therapeutic
efficacy while minimizing potential
toxicity. By its nature, TDM is pri-
marily applicable for medications
that possess narrow therapeutic
indices (ie, the drug concentration
required for therapeutic effect is
close to the toxic concentration) and
for agents that demonstrate a good
correlation between serum concen-
trations and pharmacologic effect.
Drug concentrations depend on
different factors, including drug
dosage, the pharmacokinetic proper-
ties as dictated by the function of
different organs, and genetic vari-
ability in drug metabolism. TDM
aims at achieving a drug concen-
tration within a therapeutic range.
However, it is important to note that
within the therapeutic range, some
PHARMACOLOGY
Drug Monitoring
TABLE 3.
Drug Excretion in
Human Breast Milk
DRUG M:P RATIO
Amoxicillin 0.014 to 0.043
Atenolol 1.5 to 6.8
Carbamazepine 0.6 to 0.7
Cefotaxime 0.029 to 0.16
Diazepam 0.08 to 0.13
Digoxin 0.6 to 0.8
Lithium 0.25 to 0.77
Penicillin 0.02 to 0.2
Phenytoin 0.12 to 0.24
Propranolol 0.5
Theophylline 0.57
Warfarin <0.01
M:P = milk to plasma

428 Pediatrics in Review Vol. 19 No. 12 December 1998
patients will not respond completely
and others will experience toxicity
due to pharmacokinetic and phar-
macodynamic differences among
individuals.
Appropriate timing of drug con-
centration measurement is crucial
for accurate TDM. Trough levels,
measured prior to drug administra-
tion, provide accurate interpretation
of drug concentrations. Peak levels
are less accurate because they are
subject to significant variability
due to differences in absorption and
distribution rates. Measurement of
peak levels usually is reserved for
medications that have short half-
lives in which peak levels are asso-
ciated with efficacy or toxicity.
Random sampling of drug concen-
trations is not appropriate because
the accuracy is diminished markedly.
THEOPHYLLINE
Theophylline serum concentrations
of 10 to 20 mcg/mL have been
shown to induce clinical broncho-
dilation in asthmatic children; con-
centrations of 5 to 10 mcg/mL are
effective for diaphragmatic stimula-
tion. Plasma concentrations higher
than 20 mcg/mL are associated with
an increasing incidence of toxicity.
AMINOGLYCOSIDES
Aminoglycoside-induced ototoxicity
and nephrotoxicity are closely
related to peak serum concentra-
tions. Prolonged peak levels of gen-
tamicin of 12 to 14 mcg/mL and/or
trough levels above 2 mcg/mL have
been shown to increase the risk
of both toxicities significantly.
CHLORAMPHENICOL
Chloramphenicol serum concentra-
tions of 25 mcg/mL or higher have
been demonstrated to increase the
risk for reversible bone marrow
suppression. However, this toxicity
should be distinguished from the
rare idiosyncratic form of chloram-
phenicol-induced bone marrow sup-
pression, which has no correlation
with serum concentrations.
VANCOMYCIN
Vancomycin-induced nephrotoxicity
and ototoxicity are dose-related.
Although the relationship between a
threshold serum concentration and
both toxicities is difficult to deter-
mine, trough concentrations greater
than 30 mg/L and 80 to 100 mg/L
are associated with an increased risk
for nephrotoxicity and ototoxicity,
respectively.
Summary
From a pharmacotherapy perspec-
tive, the process of development
and growth represents an unstable
and dynamic condition. Age-related
changes in drug absorption, distri-
bution, and metabolism among
neonates, infants, and prepubescent
children create a unique situation
that may increase drug toxicity of
some agents and protect from toxic-
ity of other agents. Understanding
the age-related changes in drug
disposition that are relevant for
therapeutic response and toxicity
is essential for optimizing pharma-
cotherapy at different stages of
childhood.
SUGGESTED READING
American Academy of Pediatrics. Committee
on Drugs. Transfer of drugs and other
chemicals into human milk. Pediatrics.
1994;93:137150
Brodie MJ, Feely J. Adverse drug interaction.
Br Med J. 1988;296:845849
Kearns GL, Reed MD. Clinical pharmacoki-
netics in infants and children: a reap-
praisal. Clin Pharmacokinet. 1989;17S1:
2667
MacLeod SM, Radde IC. Textbook of Pedi-
atric Clinical Pharmacology. Littleton,
Mass: PSG Publishing; 1993
Maxwell GM. Principles in Pediatric Phar-
macology. New York, NY: Oxford Univer-
sity Press; 1984
Naranjo CA, Busto U, Sellers EM. A method
for estimating the probability of adverse
drug reactions. Clin Pharm Ther. 1981;30:
239245
Stewart CF, Hampton EM. Effect of matura-
tion on drug disposition in pediatric
patients. Clin Pharm. 1987;6:548564
PHARMACOLOGY
Drug Monitoring
PIR QUIZ
17. Which of the following drugs is
contraindicated for use by the
breastfeeding mother?
A. Carbamazepine.
B. Ergotamine.
C. Propylthiouracil.
D. Phenytoin.
E. Valproic acid.
18. Which of the following is not
an inhibitor of hepatic drug
metabolism?
A. Cimetidine.
B. Ciprofloxacin.
C. Erythromycin.
D. Omeprazole.
E. Theophylline.
19. Because of decreased drug protein
binding in newborns and infants
compared with adults, increased
free drug concentrations in neonates
may result in greater drug effect
or even toxicity despite normal
total drug concentrations. This
phenomenon is true of each of
the following drugs except:
A. Digoxin.
B. Morphine.
C. Phenobarbital.
D. Phenytoin.
E. Salicylates.
20. The oral bioavailability of tricyclic
antidepressants is enhanced by:
A. Drug damage to the intestinal
absorptive surface.
B. Drug interactions in the
gastrointestinal tract.
C. Drugs that decrease hepatic
blood flow.
D. Pharmacologic delay of gastric
emptying.
E. Pharmacologic enhancement of
gastric emptying.
21. The bioavailability of which of
the following drugs is increased
in neonates compared with older
children?
A. Ampicillin.
B. Diazepam.
C. Digoxin.
D. Phenobarbital.
E. Phenytoin.