middle old, >85 yr: old old)
organ function have allowed gaining a much greater appreciation of the differences in drug disposition in pediatrics when compared with adults. Numerous recent review articles have addressed in detail clinical PK in infants and children (2,9-11).
In this chapter some changes that are pertinent in the development of pediatric dosage forms will be highlighted.
Age affects the capacity of all the physiological functions of the gastrointestinal (GI) tract (gastric acidity, gastric emptying, intestinal motility, activity of GI enzymes, biliary function, surface area, and maturation of the mucosal membrane), which can affect the rate and extent of absorption of drugs depending on the physicochemical properties of the drug and its dosage form. Except for the first hours or days, neonates have neutral gastric pH, which slowly falls to reach adult values. Acid output on a kilogram basis is similar to adult levels by age 24 months (12). Premature babies have little or no free acid during the first fortnight of life (2). Enteral feedings influence gastric acid secretion (13). This suggests that hospitalized neonates receiving only parenteral nutrition will be relatively achlorhydric. This hypothesis is supported by reports of increased absorption of acid-labile drugs in the newborn period (14).
Gastric-emptying time and intestinal transit time are reduced and erratic in neonates. Gastric-emptying time is influenced by gestational and postnatal age and the type and frequency of feeding (15). Although there is some controversy over the postnatal age at which adult patterns are attained, it is generally accepted that the rate at which most drugs are absorbed may be expected to be slower in neonates and young infants and that adult values are reached by ages six to eight months. There have been reports of erratic absorption of sustained-release products in children up to age six years (16), but the possible role of gastric emptying on this clinical finding is unknown.
Pancreatic enzyme activity is very low in premature neonates. Lipase activity increases 10-fold in the first nine months of life, whereas amylase activity increases 200fold. Since concentration of bile salts is also low in neonate and infants, it is anticipated that lipid-soluble vitamins and drugs would be poorly absorbed in early infancy (9).
The first-pass effect has not been extensively evaluated in infants and children. The maturational rate of metabolic pathways would be directly related to the oral bioavailability of a drug subject to first-pass effect. Drugs that undergo glucuronidation during enterohepatic recirculation may have altered systemic availability in children up to approximately age three years because of delayed maturation of conjugation.
Colonization and metabolic activity of GI bacterial flora do not approach adult values until ages two to four years (17). This has resulted in increased bioavailability of digoxin in infants and young children (18). The absorption of vitamin K depends, to some extent, on the development of intestinal flora as it synthesizes large amounts of menaquinones, which are potentially available as a source of vitamin K.
Drugs absorbed by active transport mechanisms appear to have a delayed rate, but not extent of absorption, in the neonatal period (17). Drug absorption is highly variable and unpredictable in neonates and infants (19,20). Older children appear to have absorption patterns similar to adults unless chronic illness or surgical procedures alter absorption. Differences in bile excretion, bowel length, and surface area probably contribute to the reduced bioavailability of cyclosporine seen in pediatric liver transplant patients (21). Impaired absorption has also been observed in severely malnourished children (22). A rapid GI transit time may contribute to the malabsorption of carbamazepine tablets, which has been reported in a child (23).
Significant changes occur in amount of body water, fat, and protein from the neonatal period through adulthood (24). The most rapid changes of relative percentage of total body water and extracellular water occur in early life (25,26), with values decreasing to approach adult levels by age 12 years (24). Water-soluble substances such as aminoglycosides will then have a greater volume of distribution and would require a larger dose in neonates; inversely a decrease in volume of distribution could be expected from a lipid-soluble drug such as diazepam (27). Adult levels of total body water and fat content are reached in adolescence (24). Plasma protein binding is altered in neonates and young infant due to a decrease of total protein, albumin, and a-1 acid glycoprotein and the presence of fetal albumin and competing substances such as bilirubin, resulting in relatively high levels of circulating free drug (26). This is especially important for highly bound drugs (e.g., phenytoin, phenobarbital, furosemide), which may require a lower total plasma concentration to achieve therapeutic effects. Malnourished children, who represent 40% of the pediatric population living in developing countries, have significantly reduced concentrations of albumin and a-1 acid glycoprotein (22).
As the blood-brain barrier (BBB) is less formed in neonate, the drug is more likely to penetrate the central nervous system (CNS).
The most noticeable changes occur in the first year of life and again at puberty. Parental exposure to inducing agents, nutritional status, and hormonal changes all play a role in metabolic activity. An added consideration is the fact that neonates requiring medications are often subject to other medical and surgical interventions that may influence drug disposition by liver (28). The underlying genetic pattern of enzymatic activity must also be considered in the assessment of dose-related effects (29).
In general, phase I reactions, such as oxidation and n-demethylation, are delayed in the neonate but mature after birth and are fully operational at or above adult levels by age six months in the full-term neonate (29-32). Cytochrome P450 (CYP) enzymes are mainly responsible for phase I reactions. Apart from CYP3A, which is already abundant in fetuses, all other CYPs develop postnatally in an enzyme-dependent fashion (9).
Phase II reactions or conjugation pathways, such as glucuronidation, do not approach adult values until ages three or four years, but there is no consistent pattern of expression. Sulfation activity does appear to reach adult levels in early infancy. For drugs that are subject to metabolism by both pathways, such as acetaminophen, the efficient activity of the sulfation pathway allows infants and children to compensate for low glucuronidation ability (33). Other compounds in which sulfation (e.g., chloramphenicol) is not an alternative pathway are subject to prolonged elimination half-lives and potential toxicity (34).
Infants and children older than one year are considered to be very efficient metabolizers of drugs and may actually require larger doses than those predicted by weight adjustment of adult doses or shorter dosing intervals (35). On the basis of metabolic activity, sustained-release formulations would appear to be ideal for children of 1 to 10 years if bioavailability issues would prove not to be problematic. The ability to clear drugs in critically ill children may be severely compromised; therefore, dosing in this subgroup of patients requires careful titration (36).
Metabolic activity declines with the onset of adolescence. After puberty, adolescents metabolize drugs at a rate similar to adults (29,37). Nevertheless, recent studies have shown that puberty, genetic polymorphism, and disease states such as cystic fibrosis also influence expression of CYP enzymes.
The renal excretion of drugs depends on glomerular filtration rate (GFR), tubular secretion, and tubular absorption. GFR is linked to the renal blood flow, which increases with age to reach adults' values at age six months. In preterm, GRF may be as low as 0.6 to 0.8 mL/min/1.73 m2, but 2 to 4 mL/min/1.73 m2 in term neonates (11). A twofold increase in GFR occurs in the first 14 days of life (38). The GFR continues to increase rapidly in the neonatal period and reaches a rate of about 86 mL/min/1.73 m2 by age three months. Children aged 3 to 13 years showed an average clearance of 134 mL/min/1.73 m2 (39). It is assumed that GFR reaches adult levels by age six months in most full-term infants (9). Tubular secretion matures at a slower rate (1 year) than glomerular function, and there is more variability observed in maturation of tubular reabsorption capacity. This is likely linked to fluctuations in lower urinary pH in the neonatal period (40).
These physiological differences lead to longer half-life in renally cleared drugs in neonates.
Differences exist in physiology and diseases, which may affect PK/pharmacodynamics (PD) in children (41). These differences are often associated with developmental growth and maturation processes. It is evident from the foregoing discussion that the greatest effects of maturation on drug disposition are observed in the first six months of life. However, individual variation in maturation in the first three years necessitates individual monitoring in the ill neonate, the infant, and the young child. Pediatric formulations that readily provide flexible doses would greatly facilitate dosing in this age group.
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