Wednesday, December 28, 2011

An Infant is not Just a Small Child

From Expert Review of Clinical Pharmacology Clinical Pharmacology in Neonates and Young Infants The Benefit of a Population-tailored Approach John van den Anker; Karel Allegaert Authors and Disclosures Posted: 12/22/2011; Expert Rev Clin Pharmacol. 2012;5(1):5-8. © 2012 Expert Reviews Ltd. Print This Email this An Infant is not Just a Small Child Tailored Pharmacokinetic Studies in Infancy: Improved Sampling Strategies & Data An Infant is not Just a Small Child John van den Anker; Karel Allegaert Posted: 12/22/2011; Expert Rev Clin Pharmacol. 2012;5(1):5-8. © 2012 Expert Reviews Ltd. The most essential characteristics of childhood are growth and maturation. Both phenomena are most prominent during infancy, making the claim that 'an infant is not just a small child' as relevant as the more commonly used paradigm that 'a child is not just a small adult'. There is already one log size difference in weight (0.5–5 kg) within the neonatal population, quite similar to the log size spectrum (5–50 kg) of childhood. The birth weight increases by 50% in the first 6 weeks of life, and doubles in the first 4 months to be three-times higher at the end of infancy. In this same time interval, there is a fourfold increase in caloric needs. As a consequence, the first year of human life is characterized by a very dynamic biological system where growth, maturation and extensive variability are the key issues. From a clinical pharmacology perspective, the consequence of such a dynamic setting is extensive interindividual variability throughout infancy in both the pharmacokinetics and pharmacodynamics of xenobiotics. Instead of median values for pharmacokinetic estimates or outcome variables, the range and its contributing covariates are crucial. Body composition and compartment sizes change during infancy, and all phase I (e.g., cytochromes) and phase II (e.g., glucuronidation) metabolic processes mature in an iso-enzyme-specific pattern, while renal function (glomerular filtration rate and tubular absorption/excretion) also displays age-dependent capacity. The phenotypic variability in either drug disposition or effects during infancy is further affected by the contribution of other, non-ontogeny-related covariates (e.g., perinatal asphyxia with whole body cooling, comedication, genetic polymorphisms, sepsis or inflammation, and congenital renal impairment). History provides the community with compound-specific observations to illustrate the negative impact of exposure to chloramphenicol (deficient glucuronidation capacity resulting in chloramphenicol accumulation and gray baby syndrome), benzyl alcohol (deficient alcohol dehydrogenase activity resulting in benzyl alcohol accumulation and gasping syndrome) or – much more recently – dexamethasone (specific vulnerability of neonatal cortical and subcortical nervous tissues, resulting in cerebral palsy and blunted brain growth) in neonates. All these anecdotic observations can be considered as illustrations of failure to consider the specific characteristics of this vulnerable population. However, optimism is a moral duty. Implementation of the pediatric regulation in the USA in 1997 has resulted in a rebirth of pediatric product development, including drugs for infants. Subsequent implementation of a similar pediatric legislation initiative in the EU (2007) and in WHO initiatives (e.g., the WHO 'make drugs child size' program, which is an ongoing program of the WHO and resulted in an essential medicines list for children in 2011) further stimulated all stakeholders (industry, academia, governmental and research organizations) to develop focused pediatric research activities. As an illustration, a search for 'newborn/infant' on the website in early October 2011 resulted in 1318 protocols for interventional studies, of which 899 were initiated (based on the sponsor's location) in the USA and 376 in Europe. Although this is only a snapshot of the ongoing clinical research activities, it suggests that there is growing research activity aiming to further improve pharmacotherapy.In addition to compound-specific observations, such studies also stimulated the development and validation of research tools in the field of pharmacokinetics (e.g., analytical techniques and population pharmacokinetics) and pharmacodynamics (population-specific 'biomarkers') adapted to newborns and infants.

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