A novel approach in pediatric drug design: the conventional pig as juvenile animal model

Background To date, the pediatric subpopulation is often neglected during drug development. The main reasons are limited economic profit of drugs adapted to children, ethical concerns for performing pediatric clinical trials and lack of appropriate preclinical animal models and methodologies, taking maturation and metabolic development into account. Lack of clinical trials and consequently the lack of pediatric formulations frequently leads to off-label use of drugs in the pediatric subpopulation, which may lead to inappropriate dosage regimens and/or increased toxicity (Kimland et al, 2012). Since children are no small adults, extrapolation from adult clinical trials is not recommended. Therefore other strategies, such as suited animal models taking growth and maturation into account, should be investigated. Traditional animal models including rodents, dogs and non-human primates, have already been explored, but seem to be insufficient due to either differences in physiology and ADME processes or ethical concerns. The aim of the present study was to determine whether the conventional pig could be a feasible juvenile animal model to study the pharmacokinetic processes of drugs, since its striking anatomical and physiological resemblances with humans. More specifically, the ontogeny of the glomerular filtration rate (GFR) and cytochrome P450 (CYP450) liver enzymes was assessed and compared to human maturation data. Methods An extensive literature search was performed based on the comparative anatomy and physiology of pigs and humans. The main focus of this meta-analysis was growth and ontogeny of the major organ systems involved in the pharmacokinetic processes of drugs, namely gastro-intestinal tract, liver and kidney. The GFR of conventional pigs was determined in four age categories using three different techniques, namely creatinine clearance in plasma and urine determined with Jaffe reaction and enzymatic method, and clearance of exo-iohexol. The ontogeny of the CYP450 enzymes was determined by in vitro activity experiments in liver microsomes of the same age categories next to the determination of the amount of CYP proteins by high definition data directed analysis (HD-DDA) mass spectrometry. Results and conclusion Literature reports demonstrated that developmental variability in ADME processes was most pronounced at birth and neonatal stage of life. The piglet might be a more appropriate juvenile animal model for PK studies when reaching infancy. An easy-to-apply creatinine equation was developed to estimate the GFR in growing piglets and to provide a useful tool in preclinical porcine studies. Furthermore, the maturation profile of GFR in piglets was comparable to humans. The in vitro metabolic capacity of the CYP enzymes increased with age which is probably due to maturation of the enzymes itself as well as to an increase in absolute amount of CYP proteins. These data supports the use of the conventional pig as juvenile animal model, although additional studies are required to fully elucidate the suitability of the piglet preclinical animal model. Reference Kimland E, Odlind V. Off-Label drug use in pediatric patients. Clin Pharmacol Ther 2012; 91: 796-801. Acknowledgements This study was supported by the Agency for Innovation by Science and Technology in Flanders through the 'SAFEPEDRUG' project (IWT/SBO 130033; IWT 141427).

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