Tamara van Donge

Chapter 3 14 this transformation takes place in the liver. Drug-metabolizing enzymes, specifically cytochrome P450 (CYP) enzymes, are converting the compound into a more hydrophilic form. These metabolites can be either pharmacological active or inactive. Finally, the parent drug and/or its metabolites are removed from the body via excretion, usually through glomerular filtration by the kidneys. Biliary or fecal excretion are other (minor) forms of excretion. Quantitative clinical pharmacology Developmental pharmacology Pediatric drug development Pediatric pharmacometrics • Pharmacokinetics ; movement of the drug into, through and out of the body (absorption, distribution, metabolism, excretion) • Pharmacodynamics ; the effect of the drug on the body (wanted and unwanted effects) • Translation of biomarkers to clinical application, tailored to pediatric population (including physiological changes) • Understanding and integrating of the role of ontogeny in the disposition of drugs • Benefit-risk balance (efficacy and toxicity) • High percentage off-label drug use in newborns and infants • EU Pediatric Regulation 2007 ensured positive impact on pediatric drug development • Understand age-related factors influencing drug disposition • Quantification of maturation processes • Predict exposure and response by simulating various scenarios which are not yet clinically investigated Figure 1: From quantitative clinical pharmacology towards pediatric pharmacometric approaches to guide neonatal and pediatric pharmacotherapy. Developmental pharmacology – pediatric physiology and pharmacology “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” – Dr. Abraham Jacobi. 4,5 This statement of Dr. Abraham Jacobi, a German physician and pioneer of pediatrics opening the first children’s clinic in the United States (US), demonstrates the foundation of developmental pharmacology and highlights the importance of the alteration of pharmacological processes with age. 6 The general principles of pharmacology also apply to newborns, infants and children, although a population focused approach is needed because of their physiological characteristics. 5,7 Measuring the efficacy and detecting an adverse drug reaction during early infancy still remains challenging. 8,9 The PK profile of a drug can therefore act as a surrogate and can be considered as a first and crucial step to determine and explore efficacy and safety in pediatric populations.