A Practical Approach, Second Edition=Ronald D. Ho.pdf

266 DEVELOPMENTAL REPRODUCTIVE TOXICOLOGY: A PRACTICAL APPROACH, SECOND EDITION“Pediatrics does not deal with miniature men and women, with reduced doses and the same classof disease in smaller bodies, but…its own independent range and horizon.” 5Traditionally, physicians have recognized that tissues and organs in children mature and functiondifferently depending on the developmental period of life, and that anomalies in these earlydevelopmental processes could be associated with disease progression found specifically in thepediatric population. 6 Despite the known differences in the physiological ontogeny from early childdevelopment to adulthood, there was very little difference in the way in which drugs were prescribedbetween the pediatric and adult populations. 7Prior to the increased concern of off-label use of drugs in children, as well the considerationfor using developmental pharmacology in the therapeutic evaluation process, there was a lack ofappropriate drug-dosing guidelines to help in the determination of pediatric drug dose levels to beused in the clinic. 8 Typically, adjustments for drug dose in children were based upon rudimentaryformulary calculations that used age or relative body size (e.g., Young’s Rule, Cowling’s Rule, orClark’s Rule), as well as labeling information derived from both nonclinical and clinical adultstudies. 9,10 These practices were based upon default assumptions that there are no developmentaldifferences for a drug’s pharmacokinetic or pharmacodynamic characteristics between children andadults, and that children and adults have similar disease progression. However, pediatric growthand development are not one-dimensional processes, and age-associated changes in body compositionand organ development and function are variables that can have an impact on drug toxicityand/or efficacy, as well as on disease progression. 9 Therefore, these prescribing practices were notconsidered sufficient for individualizing drug doses across the entire course of pediatric development.8 As a result, the use of dose level equations is being replaced by normalization of the drugdose for either body weight or body-surface area, in combination with understanding the safetyand pharmacokinetic data obtained from testing drugs in pediatric clinical trials and/or from juvenileanimal studies. 8,11–131. Historical Perspective of Pediatric TherapeuticsMany prescription drugs and biological therapeutics are marketed with little or no dosage informationfor administration to pediatric patients. This information, if available for use in the pediatric population,is provided to physicians in the product label (package insert). Therefore, the drugs without adequatelabeling information which are given to children are unlicensed or prescribed off-label. The off-labelprescription of a drug therapy approved by the U.S. Food and Drug Administration (FDA) to a patientoutside the specification of the product license involves drugs being administered by an unapprovedroute, formulation, or dosage, or outside an indicated age range. 14 According to a report in the FDAConsumer Magazine, some classes of drugs and biologics, such as vaccines and antibiotics, generallyhave adequate labeling information for pediatric use. 15 However, pediatric labeling for other classes ofdrugs has been deficient. Examples include steroids to treat chronic lung disease in preterm neonates, 16agents to treat gastrointestinal disorders, 17,18 prescription pain medications, 19 antihypertensives, 20 andantidepressants. 21 In addition, some age groups have less labeling information available to them thanothers. For example, children under 2 years of age have virtually no pediatric use information on drugproducts in several drug class categories. 22Despite regulatory efforts to increase the rate of labeling of pharmaceuticals for pediatricindications, little has changed in the way that these products are prescribed for off-label use in thepast two decades. According to some literature, more than half of the drugs approved every yearthat are likely to be used in children are not adequately tested or labeled for treating patients inthe pediatric population. 15 A survey of the 1973 Physicians’ Desk Reference (PDR) showed that78% of drugs listed contained either a disclaimer or lacked sufficient dose information for pediatricuse. 23 A later survey of the 1991 PDR indicated that 81% of the listed medications contained informationdisclaiming use in children or limiting use to specific age groups in the pediatric population. 24 Another© 2006 by Taylor & Francis Group, LLC