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MEDICAL BIOLOGY: DEVELOPMENTAL PHARMACOLOGY

The following points are made by G.L. Kearns et al (New Engl. J. Med. 2003 349:1157):

1) Infants and children are far different from adults in terms of societal, psychosocial, behavioral, and medical perspectives. More than 100 years ago, Abraham Jacobi (1830-1919), the father of American pediatrics, recognized the importance of and need for age-appropriate pharmacotherapy when he wrote, "Pediatrics does not deal with miniature men and women, with reduced doses and the same class of disease in smaller bodies, but has its own independent range and horizon."(1) As our knowledge of normal growth and development has increased in the past several decades, so has our recognition that developmental changes profoundly affect the responses to medications and produce a need for age-dependent adjustments in doses.

2) Before the integration of developmental pharmacology into clinical and therapeutic decision making, numerous approaches to determining pediatric drug doses were recommended (e.g., formulas such as Young's rule and Clark's rule). Some of these approaches use discrete age points, whereas others use allometric principles (i.e., those based on relative body size) that generally assume there are predictable, linear relations between mass (e.g., cell mass and body weight) and body-surface area among infants, children, adolescents, and adults.(2) However, human growth is not a linear process; age-associated changes in body composition and organ function are dynamic and can be discordant during the first decade of life. Thus, simplified dosing approaches are not adequate for individualizing drug doses across the span of childhood.(3) As a result, the use of dosing equations has largely been replaced by adjustment (or normalization) of the drug dose for either body weight or body-surface area. Although such guidelines are generally adequate for initiating therapy, they may fall short when it comes to continued or long-term treatment, since maintenance therapy must be individualized on the basis of developmental differences in pharmacokinetics, pharmacodynamics, or both. Thus, the provision of safe and effective drug therapy for children requires a fundamental understanding and integration of the role of ontogeny in the disposition and actions of drugs.

3) A variety of methods are used to administer drugs to children, the most common of which involve extravascular routes. A therapeutic agent administered by means of any extravascular route must overcome chemical, physical, mechanical, and biologic barriers in order to be absorbed. Developmental changes in absorptive surfaces such as the gastrointestinal tract, skin, and pulmonary tree can influence the rate and extent of the bioavailability of a drug.

4) Most drugs are administered orally to children. Changes in the intraluminal pH in different segments of the gastrointestinal tract can directly affect both the stability and the degree of ionization of a drug, thus influencing the relative amount of drug available for absorption. During the neonatal period, intragastric pH is relatively elevated (greater than 4) consequent to reductions in both basal acid output and the total volume of gastric secretions.(4,5) Thus, oral administration of acid-labile compounds such as penicillin G produces greater bioavailability in neonates than in older infants and children. In contrast, drugs that are weak acids, such as phenobarbital, may require larger oral doses in the very young in order to achieve therapeutic plasma levels. In addition, the ability to solubilize and subsequently absorb lipophilic drugs can be influenced by age-dependent changes in biliary function. Immature conjugation and transport of bile salts into the intestinal lumen result in low intraduodenal levels despite the presence of blood levels that exceed those of adults.

References (abridged):

1. Halpern SA. American pediatrics: the social dynamic of professionalism, 1880–1980. Berkeley: University of California Press, 1988:52

2. Drug dosage in children. In: Ritschel WA. Handbook of basic pharmacokinetics. 2nd ed. Hamilton, Ill.: Drug Intelligence, 1980:296-310

3. Kearns GL. Impact of developmental pharmacology on pediatric study design: overcoming the challenges. J Allergy Clin Immunol 2000;106:Suppl:S128-S138

4. Agunod M, Yamaguchi N, Lopez R, Luhby AL, Glass GB. Correlative study of hydrochloric acid, pepsin, and intrinsic factor secretion in newborns and infants. Am J Dig Dis 1969;14:400-414

5. Rodbro P, Krasilnikoff PA, Christiansen PM. Parietal cell secretory function in early childhood. Scand J Gastroenterol 1967;2:209-213

New Engl. J. Med. http://www.nejm.org

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