Environmental Health Perspectives Volume
102, Supplement 11, December 1994
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Pharmacokinetics in the Infant
Rebecca L. Milsap and William J. Jusko
Department of Pharmaceutics, School of Pharmacy, State University of
New York at Buffalo, Buffalo, New York
Abstract
Processes controlling the absorption, distribution, metabolism, excretion,
and pharmacologic effects of drugs are likely to be immature or altered
in neonates and infants. Absorption may be affected by differences in gastric
pH and stomach emptying rate. Low serum protein concentrations and higher
body water composition can change drug distribution. Drug metabolism enzyme
activity is typically reduced in the neonate, but rapidly develops over
the first year of life. Renal excretion mechanisms are low at birth, but
mature over a few months. Limited data are available on the pharmacodynamics
of drugs; infants show greater sensitivity to d-tubocurarine. Developmental
changes are rapid during the first weeks and months of life, thus requiring
continual modification of drug dosage regimens designed for treating pediatric
patients. -- Environ Health Perspect 102(Suppl 11):000-000 (1994)
Key words: pharmacokinetics, absorption, distribution, metabolism,
excretion, pharmacodynamics
This article was presented at the Workshop on Pharmacokinetics:
Defining the Dose for Risk Assessment held 4-5 March 1992 at the National
Academy of Sciences in Washington, D.C.
This work is supported in part by grant 24211 from The
National Institutes of General Medical Sciences.
Address correspondence to William J. Jusko, Department
of Pharmaceutics, School of Pharmacy, State University of New York at Buffalo,
Buffalo, NY 14260. Telephone (716) 645-2855. Fax (716) 645-3693.
Introduction
The safe and effective exposure to therapeutic drugs and inadvertant
chemicals during the first year of life presents unique challenges
to the clinician, pharmacokineticist, and toxicologist because of the rapid
changes in size, body composition, and organ function of infants during
this period. Ignorance of the unique nature of drug disposition in the neonate
led to such now preventable tragedies as gray baby syndrome from chloramphenicol,
congenital anomalies from thalidomide, and kernicterus from sulfonamides.
The area of pediatric pharmacokinetics has blossomed since the 1970s, when
advances in the development of sensitive and specific drug assays began.
Pharmacokinetic parameters such as clearance (CL), volume of distribution
(V) and half-life (t1/2) have been described for many therapeutic
agents used in the newborn and young infant (1-6) and numerous reviews
are devoted to this subject (1-12). However, quantitation of clinical
effects and pharmacodynamic response as modified by development and
disease are areas that have lagged behind description of pharmacokinetics
in this age group (10).
The information available on pediatric pharmacokinetics has demonstrated
significant differences in absorption, distribution, metabolism, and
excretion in premature neonates, full-term neonates, and older infants (Table
1). A summary of the major age-related physiologic changes that impact on
drug disposition follows.
Absorption from the Gastrointestinal Tract
Drugs administered by the oral route must move to sites of absorption
and then cross multiple gastrointestinal (GI) membranes before they pass
into systemic circulation. Most drugs appear to be absorbed by passive diffusion,
although some drugs and nutrients are absorbed by an active process (13).
Two major factors affecting the absorption of drugs are pH-dependent passive
diffusion and gastric emptying (14-17). Both processes demonstrate
a variable but age-related trend from birth well into infancy and childhood
(15,17). The neutral gastric pH (pH 6-8) at birth is related to the
presence of amniotic fluid in the stomach (14). Postnatally,
gastric acid secretory capacity appears after the first 24 to 48 hr
of life and gastric acidity decreases during the first weeks to months
of life (15). Adult values are approached by 3 months of age. In
premature infants, gastric pH may remain elevated due to immature acid secretion
(18). This higher gastric pH may explain the higher serum concentrations
of acid-labile drugs such as ampicillin, penicillin, and nafcillin observed
in neonates relative to older children and adults (19,20).
Delayed absorption of phenobarbital, phenytoin, acetaminophen, and riboflavin
occurs (13,20,21). The rate of gastric emptying during the neonatal
period is both variable and prolonged (17). Gestational age and postnatal
age both affect gastric emptying rate (17) with prolonged emptying
times seen in premature infants. Calculated rates of absorption for phenobarbital,
digoxin, xylose, and other substances have demonstrated that although prolonged
gastric emptying is present in neonates, it does not completely account
for the delays seen in gastric absorption of these compounds (13).
Figure 1 demonstrates the relationship of enteral absorption of phenobarbital
to age after a single weight-adjusted dose in children aged 10 days to 1
year. The rate constant, ka, increases with the age of the child (13).
Age-dependent differences in absorption rate remain even after stimulation
of intestinal motility. However, they demonstrate a decreased capacity of
enteral absorption in neonates; this decrease is attributable to factors
other than decreased gastric emptying time, and GI motility. Additional
physiologic activities that are diminished in the neonate are pancreatic
enzyme function and bile acid secretion (22).
Figure 1. Relationship
of enteral absorption rate contstant (ka) of phenobarbital to age during
the first year of life. Adapted from Heimann (13).
Absorption from Skin and Muscle
Percutaneous absorption may be drastically increased in neonates owning
to an immature epidermis and increased skin hydration. Toxicity because
of topical application of hexachlorophene (23) and isopropanol (24),
among other agents, has been documented. Conversely, therapeutic serum theophylline
concentrations can be obtained in premature infants by applying theophylline
gel to the skin (25). Drug absorption from an intramuscular site
may be unpredictable and decreased due to insufficient blood flow,
poor muscle tone, and compromised muscle oxygenation (3). Variable
intramuscular absorption has been demonstrated for digoxin, gentamicin,
phenobarbital, and diazepam in neonates (3,26).
Distribution
The distribution of drugs within the body is influenced most notably
by the amount and character of plasma proteins, and the relative size of
the fluid, fat, and tissue compartments of the body. Total body water,
expressed as a percentage of total body weight, is as much as 85% in preterm
and 78% in full-term neonates (27). The effect of an increased fraction
of total body water is apparent when assessing the pharmacokinetic parameter-volume
of distribution--which relates drug concentration in plasma to the remaining
portions of the body. Table 2 presents calculated Vis
for various drugs. Drugs which distribute in parallel with body water content
have higher V values for infants than adults. Conversely, a lipophilic drug
such as diazepam would have a smaller V in infants.
The binding of drugs to plasma proteins is dependent on multiple factors,
all of which may be immature in the neonate (4). During this period,
plasma albumin, total protein concentrations, and 
1-acid
glycoprotein are decreased and do not approach adult values until about
1 year of age (28,29). In addition, acid-base disturbances, competition
for binding sites by increased circulatory concentrations of endogenous
bilirubin and free fatty acids, and the qualitatively different albumin
seen during the neonatal period, alone or in concert, may all affect drug
protein binding (1,4).
Metabolism
Hepatic enzyme activity and plasma/tissue esterase activity are both
reduced during the neonatal period (3). Most enzymatic microsomal
systems responsible for drug metabolism are present at birth and their activities
increase with advancing gestational and postnatal age (3,12,30-32).
Hepatic phase I reactions (i.e., oxidation, reduction, hydroxylation) develop
rapidly during infancy, with adult capacities attained by 6 months of life
(30-32). These changes have been documented for phenobarbital, phenytoin,
diazepam, meperidine and numerous other agents (3,33). Drugs subject
to a low hepatic extraction undergo an even further reduction in metabolism
by neonates (4,12).
Phase II conjugation reactions are generally reduced at birth, although
exceptions have been demonstrated. The conjugation with glucuronic acid
is significantly depressed at birth, although a well-developed capability
for sulfate conjugation exists (20). Glycine conjugations are present
in neonates at levels comparable to those of adults (31). Enzymatic
systems responsible for theophylline oxidation and methylation to caffeine
are active in premature neonates; whereas, the development of enzymes for
oxidative demethylation do not develop for several months of life (34,35).
The variation of theophylline metabolism observed during the first
year of life is presented in Figure 2. Data compiled from multiple clinical
studies conducted in premature neonates, full-term neonates, and infants
during the first year of life, shows the interindividual variation
of theophylline clearance and its increase with age. The effect of exogenous
growth hormone administration to deficient children was associated
with a decrease in theophylline half-life in small number of patients (36).
Figure 2. Plasma
clearance of theophylline in relation to age for premature infancts (P)
and during the first year of life. Data compiled from multiple published
studies (11).
Esterase activity is depressed to a greater extent in premature infants
than term infants and does not achieve even term infant activity for 10
to 12 months postnatally. Low esterase activity coupled with a diminished
volume of distribution in the newborn may account for the prolonged effect
of local anesthetics seen during delivery (37).
A factor also to be considered is in utero exposure to enzyme
inducing agents such as barbiturates, glucocorticoids, caffeine, and tobacco
(12). Prenatal exposure to these agents may significantly alter
the disposition of such drugs as diazepam, phenobarbital, and phenytoin
after birth (12). Recently, caffeine has been identified as
a sensitive biomarker for development of the P450 monooxygenase system activity
(38) and maturation of this system during critical phases of growth
and development could be mapped. Slower biotransformation of metronidazole,
a drug metabolized by P450 enzyme system, has been demonstrated in severely
malnourished infants and children as compared to the nonmalnourished state
(39).
Renal Excretion
Significant age-dependent changes in renal function affect the elimination
of drugs and their metabolites. At birth, glomerular function is more advanced
than tubular function and this persists until 6 months of age (40-42).
The processes of glomerular filtration, tubular secretion, and tubular
reabsorption all define the efficiency with which the kidney eliminates
such drugs as tobramycin (43), netilmicin (44), mezlocillin
(45), gentamicin (46), and such other agents as glucose, phosphate,
and bicarbonate (11,40). All of these clearances may be reduced during
infancy. At birth, glomerular filtration rate (GFR) is 2 to 4 ml/min
in term neonates and as low as 0.6 to 0.8 ml/min in prematures (40-42).
Dramatic increases occur during the first 72 hr of life where GFR may
increase 4-fold (40-42). In general, the renal clearance of drugs
that parallel GFR, such as the aminoglycosides, will exhibit pharmacokinetic
changes consistent with maturation of renal function, an age dependent process.
A strong relationship has been demonstrated between mezlocillin CL and body
weight (45) (Figure 3). Further investigation has revealed that nonrenal
clearance of the antibiotic also occurs (47).
Figure 3. Mezlocillin
clearance in relation to gestational age in infants less than 1 week of
age. Clearance values for adults are shown for comparison. From Janicke
et al. (45).
Pharmacodynamics and Receptor Sensitivity
Recent technological developments have enabled the characterization of
cholinergic, adrenegic, glucocorticoid, opiate, and histamine receptors
(11,48-51). Age-related alterations in ß-receptor affinity
for adrenegic agonists has been demonstrated in the elderly (49).
The different sensitivity of the neuromuscular junction to d-tubocurarine
(d-TC) among neonates, infants, and children and adults has been
determined (52). In addition to the pharmacodynamic response, the
pharmacokinetics were also assessed. Figure 4 presents a summary of the
age-dependent variables of CL, V, t1/2 and d-tubocurarine
plasma concentration required to produce 50% paralyses. Although plasma
clearance appeared not to change with age, half-life was prolonged due to
the larger V. The distribution of d-TC parallels that of a molecule
that distributes to extracellular fluid. The plasma concentration d-TC
that correlates with 50% response was significantly lower in neonates
and infants than children and adults. Receptor sensitivity at the neuromuscular
blockade appears then to be increased with paralysis occurring at a lower
concentration in this age group.
Figure 4. Pharmacokinetic
and pharmacodynamic data from neonates, infants, children, and adults following
d-tubocurarine infusion. From Fisher at al. (52).
Data available on receptor sensitivity during the neonatal period is
limited. Extrapolation from in vitro data may not be reflective
of the true pharmacodynamic response, although data from isolated tissue
preparations provide relevant information regarding developmental and maturational
changes in receptor binding characteristics.
Drug Monitoring
Pharmacologic and toxicologic assessment during the neonatal period and
throughout infancy should appreciate not only the serum drug concentration
as an index of xenobiotic exposure, but also the stage of development of
organ function and body composition (53-55). Neonates represent the
most fragile group due to their physiological instabilities and their increased
potential for toxic effects.
In conclusion, it is readily apparent that most of the physiologic variables
influencing drug disposition are unique in the neonate and infant as
compared to children and adults. This age group should remain an active
population for concern in future pharmacokinetic, pharmacodynamic, and toxicologic
research.
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