Pharmacological research in pediatrics: From neonates to adolescents

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Abstract

The data guiding the dosing, efficacy and safety of medicines for children have lagged substantially as compared to the information available for adults. As a consequence, pediatricians faced with the prospect of confining their practice to medicines with adequate information have frequently resorted to prescribing medicines for unapproved uses (different dose, frequency, age group, route, indication or formulation). Although a long time in coming, the past decade, have witnessed a new era in drug development for children — an era that is still in its infancy, but which is currently showing signs of maturation. This review will give some of the history and current progress in pharmacological research and pediatric drug development.

Section snippets

History

The history of drug therapy is replete with examples of adverse reactions to drugs in neonates, infants, children and adolescents. In 1937, 107 people – primarily children – died after taking elixir of sulphanilamide to treat streptococcal infection. Sulphanilamide was not very water soluble, but a chemist at Massengill Co. found that it dissolved well in diethylene glycol (more commonly known as antifreeze), which is now known to be highly toxic. In 1956, Andersen et al. at Columbia reported

Off-label prescribing

At intervals since 1968, surveys have documented that only a minority of medicines receive labelling for pediatric use. Even fewer receive labelling for use by neonates and infants [6]. In the period 1973–1997, the percentage of approved drugs that contained no labelling information for children remained fairly stable at 71–81% [6]. Of the 33 new molecular entities (NMEs) approved in 1997, 27 had potential for pediatric use, but only nine contained any pediatric labelling information.

With so

Extent of off-label prescribing

Numerous surveys have documented extensive off-label drug use in hospitalized pediatric patients. Conroy et al. [7] surveyed off-label use in general pediatric wards in five European countries. Sixty-seven percent of all patients received at least one off-label prescription. ‘t Jong et al. [8] reported an even higher incidence of off-label use in a prospective 19-week survey at a general hospital in The Netherlands, at which 92% of children received at least one off-label prescription. Sicker

New developments

During the past two decades, tremendous strides have been made to tailor therapies for the needs of children. As our knowledge of normal growth and development has increased, so has our recognition that developmental changes profoundly affect the responses to medications and produce a need for age-dependent dose requirements [11].

Prior to the clinical integration of developmental pharmacology into therapeutic decision making, numerous approaches (e.g., Young's Rule, Clark's Rule) for

Absorption

For therapeutic agents administered by extravascular routes, the process of absorption is reflected by the ability of a drug to overcome chemical, physical, mechanical and biological barriers. Developmental differences in the physiologic composition and function of these barriers can alter the rate and/or extent of drug absorption. While factors influencing drug absorption are multifactorial in nature (e.g., physical, chemical and biological), developmental changes in the absorptive surfaces

Distribution

Age-dependent changes in body composition (Fig. 1) [16] alter the physiologic “spaces” into which a drug may distribute. Larger extracellular and total body water spaces in neonates and young infants, coupled with adipose stores that have a higher water / lipid ratio than in adults, produce lower plasma concentrations for drugs that distribute into these respective compartments when administered in a weight-based fashion. For lipophilic drugs that associate primarily with tissue, the influence of

Drug metabolism

Cardiovascular collapse associated with the “gray baby syndrome” in newborns treated with chloramphenicol is often cited as a clinically significant consequence of developmental deficiencies in drug metabolizing enzyme activities [17], [18]. Multiple examples exist of clinically important developmental changes in drug biotransformation sufficient to produce the need for age-appropriate dose regimen selection in neonates and young infants (e.g., methylxanthines, nafcillin, 3rd generation

Phase I enzymes

Development has a profound effect on the expression of Phase I enzymes such as the cytochromes P450 (CYPs). CYP3A7 is the predominant CYP isoform expressed in fetal liver where it may play a fetoprotective role by detoxifying dehydroepiandrosterone sulfate 49 and potentially teratogenic retinoic acid derivatives [21]. CYP3A7 expression peaks shortly after birth and then declines rapidly to levels that are undetectable in most adults [22]. Distinct patterns of isoform-specific developmental CYP

Phase II enzymes

Phase II reactions generally result in pharmacological inactivation or detoxification by conjugating xenobiotics with small molecules such as UDP-glucuronic acid, glutathion, or acetyl coenzyme A. These reactions are catalyzed by a variety of enzymes, the activity of which appears to be associated with development. While the impact of ontogeny on Phase II enzymes has not been investigated to the same extent as for Phase I enzymes, a conceptual understanding of their known developmental profiles

Renal elimination

Maturation of renal function is a dynamic process that begins early during fetal organogenesis and is complete by early childhood. The developmental increase in glomerular filtration rate (GFR) involves active nephrogenesis, a process that begins at 9 weeks and is complete by 36 weeks of gestation, followed by postnatal changes in renal and intrarenal blood flow [62]. Following birth, the GFR is approximately 2–4 ml/min/1.73 m2 in term neonates and as low as 0.6–0.8 ml/min/1.73 m2 in preterm

Conclusions

The advances in pediatric clinical pharmacology during the past decade reside with an enhanced understanding of the influence of growth and development on drug disposition and action. As this moves forward, it is essential that the ultimate goal be kept clearly in sight. Specifically, providing infants and children with safe and effective drug therapy made possible by including them in the process of development of medications essential to ensure their health.

The goal of rational drug therapy

Acknowledgements

Supported in part by grants 1K12 RR017613-03 (N.Y.R.), 1 K24 RR019729-01 (J.N.A.), National Center for Research Resources and 1 U10 HD45993-02 (J.N.A.), National Institute of Child Health and Development, Bethesda, MD.

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