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Figure 3.2 Hypothetical age-dependent changes in the therapeutic margin.
EXAMPLES OF INCREASED TOXICITY
In the growing child, chronic treatment with corticosteroids impedes linear
growth, and similar concerns have been expressed about stimulants such as
amphetamine and methylphenidate used for attention deficit/hyperactivity
disorder (ADHD).
62,63
Tetracycline antibiotics are not recommended for
children younger than 8 years of age because they cause enamel dysplasia in
developing teeth.64 The use of the fluoroquinolone antibiotics in children is
limited because of potential toxicity to growing cartilage.
65
The incidence of metoclopramide-induced dystonias and bradykinetic
reactions diminishes strikingly with maturation from ages 10 years to
adulthood, whereas neuroleptic-induced akathisia is less common in
children.66 Neuroleptic-withdrawal dyskinesias are also more common in
children.9 This may be related to greater concentration of dopamine-2
receptors in the brain of young patients.12 Alternatively, the intensity of
adverse effect maybe increased because of enhanced tissue sensitivity.
There are also examples of paradoxical responses reflecting the different
roles that neurotransmitters, receptors, and hormones play in infancy and in
the developed adult. Children younger than 1 year of age are more susceptible
to respiratory depression from weight-adjusted doses of opioid drugs, which
are generally safe in older children and adults. Codeine is now
contraindicated in children under the age of 12 years, following the
identification of cases of respiratory depression, including deaths when
codeine was used as an analgesic for postoperative pain, general pain, and
cough and cold.
67
Verapamil is used for the treatment of supraventricular arrhythmias in
older children and adult patients. However, infants with supraventricular
tachyarrhythmias appear to be at increased risk of sudden cardiac arrest. The
neonatal myocardium appears to be especially sensitive to calcium-channel
blockade with a relative deficiency of calcium channels compared with adult
myocytes, predisposing to conduction block complications. In addition, the
dynamics of calcium in excitation–contraction coupling are different in the
immature fetal and neonatal heart to those in the older child and adult. Hence,
blocking of calcium channels may have a pronounced negative effect on the
intracellular calcium concentration responsible for contraction. Verapamil is
not recommended for the treatment of acute arrhythmias in infants younger than
1 year of age.
68
Valproic acid is one of the anticonvulsants most commonly used in
children. In rare cases, it can cause acute hyperammonemia associated with
encephalopathy. Children younger than 5 years of age are at highest risk for
developing this life-threatening adverse reaction, particularly if they are
receiving concurrent therapy with other anticonvulsant drugs.
69,70
EXAMPLES OF DECREASED TOXICITY
Immaturity does not invariably predispose to increased risk of toxicity.
Although infants and children may be more susceptible than adults to certain
types of drug toxicity, there are important examples in which differences in
drug disposition appear to result in decreased risk of toxicity in immature
individuals.
Infants and young children appear to be less susceptible to ototoxicity and
renal toxicity from aminoglycoside antibiotics compared with older patients.
71
This may be due, in part, to reduced intracellular accumulation of the
aminoglycoside in renal tubular epithelial cells.
72
Hepatotoxicity from halothane is relatively rare in children, even
following multiple exposures, whereas it is not uncommon in adults.73 The
risk of isoniazid-induced hepatitis is age related.74 An incidence of 0 per
1,000 patients younger than 20 years of age was reported by the FDA,
whereas the incidence was 23 per 1,000 in patients 50 to 65 years of age.75 It
is usually unnecessary to routinely check liver function tests in children
receiving isoniazid.
SUMMARY
The prepubescent child is clearly different from the newborn infant and the
adolescent. From a pharmacotherapy perspective, the dynamic processes of
growth and development create a moving target for the prescriber. The
developmental changes in infants and children affect organ responses to both
diseases and drugs. To employ, drug therapy across the population requires a
thorough understanding of the PK–PD relationship. Hence, the key to
successful drug therapy in children is to understand the age dependency of this
relationship. This, in turn, requires that drugs are appropriately evaluated in
1.
2.
3.
4.
5.
6.
the pediatric population and that appropriate dosage regimens are designed to
compensate for developmental changes.
Whereas the age dependency of PK processes such as absorption,
distribution, metabolism, and excretion are extensively studied and delineated
for many commonly prescribed drugs, thus far, much less effort has been
afforded to investigating the age dependency of PD responses. Similar efforts
to increase and establish data on developmental PD are urgently required to
achieve optimal drug therapy in children and to ensure long-term success of
pediatric drug development. Key to such efforts is the availability of
clinically relevant and validated, age-specific PD endpoints.
Sparsely reported experimental data from animal models provide some
insight into developmental changes affecting the structure and function of
receptors, cells, tissues, and organs and, therefore, some explanation for agerelated differences in PD response. Though clinical study data are extremely
limited, together with empirical data, there is convincing evidence from a
number of therapy areas of altered efficacy in children. Also, children may be
uniquely susceptible to some types of drug toxicity while being protected from
other toxic mechanisms by their immaturity. Finally, it is also important to
remember that structure and function of organ systems, particularly the
developing brain, may be permanently affected by interaction of
pharmacologic agents with receptors during early crucial phases of
development. Therefore, the decision to use pharmacologic agents in young
children must follow careful consideration of potential long-term impact.
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Stephani L. Stancil
Alenka Chapron
Susan M. Abdel-Rahman
C H A P T E R
4
Drug Absorption, Distribution, Metabolism, Excretion, and Transporters in Newborns and Children
INTRODUCTION
Between the time that a drug is prescribed and the time it elicits an effect in
the human body, it will have encountered numerous physiologic processes that
determine the extent to which it gets in, where it goes once it enters, and how
it will be removed. Success in choosing the right drug at the right dose for the
pediatric patient is best achieved by understanding how these processes
influence the relationship between dose and exposure and, by extension,
between exposure and response. For the vast majority of therapeutic agents
administered to children, treatment focuses solely on the dose necessary to
achieve a desired response (e.g., cure from infection). Yet, any provider will
tell you that children administered the same weight-adjusted dose of a drug do
not always respond in the same way. In many cases, this can be attributed to
variations in systemic exposure that arise because of the unique constitution of
each patient and their current stage of growth and development. In this
chapter, we explore the physiologic drivers that influence absorption,
distribution, metabolism, excretion, and transport (ADMET) and describe the
current state of knowledge as to how these processes change across the
continuum of age. Prior to exploring these data, however, it is important to
TABLE 4.1
comment on their strengths and limitations so as to ensure their interpretation
in the most judicious manner possible.
The source of truth with respect to pharmacokinetic (PK) phenotype in
children derives from carefully conducted pediatric clinical studies. Powered
adequately, these studies can also confer insights into the role that
demographic, pathologic, and environmental factors play in the disposition of
the drug under investigation. Unfortunately, the relatively limited number of
pediatric PK trials that are undertaken often requires us to predict pediatric
exposures from preexisting adult PK data combined with nonclinical data
generated in animal- or cell-based systems. Juvenile animal studies provide
an avenue for predicting drug disposition in children, but caution is advised
when extrapolating data from animals to humans. First, the overall physiology
between animal models and humans can differ as can the developmental
trajectory of key disposition processes1 (for a meaningful interpretation of
animal studies, the developmental stages of selected animals relative to
human are presented in Table 4.1). Second, interspecies differences occur for
protein isoforms of various drug-metabolizing enzymes (DMEs) and
transporters.2 Despite these discrepancies, some animal models can provide
important insights into age-dependent changes in plasma and tissue
concentrations following drug administration.
Analogous De velopmental Stages Be tween Humans and Selecte d Animal
Species
Research conducted in vitro in human tissues can also contribute to our
understanding of pediatric drug disposition. Though largely devoid of
ancillary physiologic influences, these models allow us to characterize
developmental variations in the expression levels and activity of DMEs and
transporters and to define the mechanistic basis behind intrinsic and extrinsic
modulators of activity that may be present at discrete ages. Quantitation of