Clinical Pharmacokinetics in Infants and Children

Abstract

Wide variations in drug dose recommendations for children of the same or different ages reflect the inadequacy of data on pharmacokinetics and pharmacodynamics in children. Selected aspects of available literature on pharmacokinetics of drugs used in older infants and children has been reviewed with special attention to calculation of an age-appropriate dose. During the neonatal period and early infancy the elimination of many drugs that are excreted in the urine in unchanged form is restricted by the immaturity of glomerular filtration and renal tubular secretion. On the other hand, in late infancy and/or in childhood, a similar or greater rate of elimination from plasma than in adults has been observed for many drugs, notably digoxin, phenobarbitone, phenytoin, carbamazepine, ethosuximide, diazoxide, clindamycin and propoxyphene. Consistent with this, it has been shown that some drugs exhibit a lower plasma level/dose ratio in infancy and early childhood as compared with the adult. This is true for phenobarbitone, phenytoin and ethosuximide. Some age groups of children remain uninvestigated with regard to pharmacokinetics, even for the drugs reviewed. Therefore, pediatric therapy remains empirically based for many drugs.

A study of the disposition of alpha‐methyldopa in newborn infants following its administration to the mother for the treatment of hypertension during pregnancy.

“…Thus, the amounts of a-methyldopa determined in the urine provide an uncertain indication of the amount of drug in the newborn infant. The body load of oa-methyldopa at birth has been estimated from the body weight and umbilical cord plasma concentration of the drug (Table 2) assuming that the free and conjugated a-methyldopa is distributed throughout the extra-cellular water at these concentrations; the extracellular water in the neonate being taken to equal 40% of the birth weight (Rane & Wilson, 1976). These estimates of the amount of free and conjugated oa-methyldopa in the infants at birth vary between 130-850 jg (mean 442 jg) and 275-1630 jg (mean 692 ig) respectively.…”

Morphine metabolism in children.

“…There have been no studies of the metabolism of morphine in children or neonates. The metabolism of drugs by children is different from that of adults (Rane & Wilson, 1976;Rane, 1989), with age dependent differences for drugs that undergo oxidation (phenytoin, theophylline) as well as for drugs that undergo conjugation (oxazepam) (Tomson et al, 1979). A decreased ability to conjugate paracetamol with glucuronic acid, with increased conjugation to paracetamol sulphate has been reported in prepubertal children (Miller et al, 1976) and in foetal liver preparations (Rollins et al, 1979).…”

Passage of paracetamol into breast milk and its subsequent metabolism by the neonate.

“…It is believed to present no risk to the suckling infant since less than 0.25% of a maternal single dose is estimated to reach the child (Berlin et al, 1980;Bitzen et al, 1981). As many drug metabolic reactions are deficient in the newborn (Rane & Wilson, 1983), ingestion of seemingly small quantities of drug may assume importance. Levy et al (1975) and Miller et al (1976) found that neonates had limited capacity to conjugate paracetamol with glucuronic acid but that sulphate conjugation was well developed.…”