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O-35 A novel approach in paediatric drug design: the conventional pig as juvenile animal model
  1. Millecam,
  2. Gasthuys,
  3. Devreese
  1. Croubels Ghent University, MERELBEKE, Belgium

Abstract

Background To date, the paediatric subpopulation is often neglected during drug development. The main reasons are limited economic profit of drugs adapted to children, ethical concerns for performing paediatric clinical trials and lack of appropriate preclinical animal models and methodologies, taking maturation and metabolic de-velopment into account. Lack of clinical trials and conse-quently the lack of paediatric formulations frequently leads to off-label use of drugs in the paediatric 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 mod-els including rodents, dogs and non-human primates, have already been explored, but seem to be insufficient due to either differences in physiology and ADME pro-cesses 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 pharma-cokinetic processes of drugs, since its striking anatomi-cal 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 clear-ance 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 Literature reports demonstrated that devel-opmental 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 pig-lets 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.

Conclusion These data supports the use of the conven-tional pig as juvenile animal model, although additional studies are required to fully elucidate the suitability of the piglet preclinical animal model.

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