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Pediatric Considerations

The physiologic processes that determine drug disposition undergo radical changes during biological maturation[2,3,4]. Thus, the processes of drug absorption, distribution, metabolism, and excretion are modified throughout infancy and childhood. These changes mean that a) drug disposition both changes during maturation and differs from biological norms, and b) a large inter patient variability in drug disposition is observed for many drugs in this patient population.

Further complications are that little data is available concerning the disposition of drugs in infants before the general release of new drugs. Also studies in infants and young children are difficult to perform because of the limited amount of sample which can be collected. The most dramatic changes occur in the first year, thereafter dose adjustments can be made on a weight or surface area basis without too many problems.

Pharmacokinetic changes


Infants after the newborn period have a relative achlorhydria; with gastric acid secretions increasing to reach adult levels at age 3. The bioavailability of acid labile penicillins is increased in newborns.
Delayed gastric emptying and irregular intestinal peristalsis leads to slower absorption of some drugs in infants and young children.


Total body water as a fraction of body weight decreases throughout the first year of life (see the Table XXI-3).

Extravascular fluid is proportionately higher at earlier age as well. In general distribution volumes expressed as volume per body weight tend to be larger in neonates than in adults and decrease towards adult values during childhood. This has been observed for ampicillin, ticarcillin, and amikacin. Binding to plasma proteins appears to be less in newborn infants compared with older children and adults. This appears to be true for both acidic and basic drugs. The presence of competing substances, such as bilirubin in premature infants, complicates the picture.


The various pathways of drug metabolism mature at different rates, and therefore the ability of the newborn to metabolize drugs differs both quantitatively and qualitatively from that of older subjects. No general rules can be developed and a few examples can illustrate the variety of effects observed.

Caffeine is very slowly metabolized in newborns. During the first month almost no metabolism occurs, with half-lives of about 4 days resulting from renal elimination, normally a minor pathway. Between 3 and 7 months, caffeine is metabolized similarly to adults and the half-lives change to adult values during this period. For the similar compound theophylline the half-life was 13 to 29 hours for 8 low birth weight infants.

Glucuronidation is quite inefficient at birth, thus chloramphenicol which is normally glucuronidated in adults and has no major alternate metabolic pathway, the overall elimination is much slower in newborns compared with adults.

Sulfate conjugation is well developed at birth thus newborn paracetamol elimination, predominantly sulfation, is not greatly different from that of adult elimination.

For drugs which undergo M-M or saturable metabolism the effect of age is interesting. For phenytoin, Km is not changed with age, but the maximum metabolism rate, Vm falls progressively with younger patients.


Glomerular filtration and renal tubule function in premature infants and newborns is somewhat immature. GFR, normalized for body surface area, increases gradually reaching adult values at about 6 months.

Table XXI-2 Glomerular Filtration Rate at Various Ages

AgeGFR (ml/min/m2)
First four days1
14 days22
One year70

Renal tubular capacity, measured by renal clearance of p -aminohippurate, achieve adult values 1 to 2 months later. Therefore drugs which depend primarily on the renal route of elimination, such as gentamicin, ampicillin, and furosemide, have prolonged elimination times in neonates and young infants.

Table XXI-3 Physiologic Differences between Neonates and Adults of Pharmacokinetic Importance[5]

Gastric acid output (mEq/10kg/hr)0.152
Gastric emptying time (min)8765
Total body water (% of body weight)7860
Extracellular water (% of b.wt.)4419
Intracellular water (% of b.wt.)3441
Adipose tissue (% of b.wt.)1212-25
Serum albumin (gm/dL)3.74.5
Glomerular filtration rate (ml/min/m2)1170

Table XXI-4 Pharmacokinetic Parameter Values for Infants and Children compared with Adult values[6]

Age groupVolume term
Total body clearance
Premature neonates0.62
GentamicinVcTBC (ml/min/1.73 m2)
Preterm infants and full-term infants0.485.721.0
Infants and children0.281.4130
ChloramphenicolVdTBC (ml/hr/kg)
Infants (11-56 d)10
Infants (1-12 mo)0.90 5.550-400
Children (1-11 yr)0.904.4100-400

Dosing recommendations

For some drugs detailed pharmacokinetics development of dosage regimens for pediatric patients is not practical. Either there isn't enough good data to make an accurate estimate of dose regimen or there is too much intra- patient variability in parameter values. Alternately, dosage regimens can be determined from various reference texts such the Pediatric Dosage Book. For very young infants and neonates the primary literature should be consulted.

Minimal adjustments can be based on weight, surface body area, or age. Dosing based on weight, e.g. per mg doses or Clark's rule

Dosing based on surface area, e.g. per m2

Dosing based on age, e.g. Young's rule for children older than 2 years

This page was last modified: 12 February 2001

Copyright 2001 David W.A. Bourne

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