Translating animal research from the laboratory to the neonatal clinical arena requires great caution

Biomedical studies play an important role in the process of drug discovery and development, and animals have commonly been used to study the effects of pharmacological interventions. Extensive biomedical and clinical studies are required to investigate the pharmacokinetics and pharmacodynamics of drugs in adults, in order to ensure high-quality dosing regimens and safe and effective drug administration. However, more than 50% of the medication used for European children has not been adequately tested and is not authorised for paediatric use 1. Despite the notion that children are not small adults, converting the dosing regimens for adults as per kilogram of body weight or per square metre of surface area is often used to calculate paediatric dosing regimens. This empirical procedure may have oversimplified the dosing regimen in children, which is complicated by the ontogenic development in pharmacokinetics and pharmacodynamics, from child to adult. Moreover, the pharmacokinetics and pharmacodynamics of therapeutic interventions are confounded by the feto-neonatal transition in the first days after birth and by associated pathologic conditions. That is why the European Parliament and Council issued Regulation (EC) No 1901/2006 on medicinal products in 2006, which covers the application of drugs to the paediatric population, from birth to 18 years, in order to restrict off-label drug use and prevent inadequate treatment and adverse drug reactions 2. This regulation aims to ensure safe and effective medicinal products for children through further relevant research. In this issue of Acta Paediatrica, Rasmussen et al. report interspecies differences in the pharmacokinetics of dopamine. They report that newborn piglets metabolised dopamine more rapidly than human neonates, with an increase in plasma clearance of more than 1.5-fold 3. The newborn piglet model is the most commonly used, nonrodent animal model in neonatal cardiovascular research, because of the close similarity with human neonates. Chapados and Cheung previously commented on the appropriateness of different animal models with regard to intraspecies differences, for example between domestic pigs and minipigs, interspecies differences, such as piglets and lambs, and ontogenic differences between neonates, children and adults 4. The Rasmussen et al. study was nicely designed to address the original and interesting question of interspecies differences in dopamine pharmacokinetics using state-of-the-art methodologies, and the information is important. Indeed, many researchers have also observed that piglets required higher doses of dopamine than neonates to achieve similar effects on blood pressure. While using blood pressure as an outcome measurement of dopamine administration is controversial, given the possible diversity in the actions of dopamine, we should also look at the interspecies and ontogenic differences in pharmacodynamics. Rey-Santano et al. compared the effects of fentanyl in newborn piglets and human neonates and observed differences in the effects on their heart rate, cerebral blood flow and oxygen metabolism, but not on ventilation and sedation 5. Little information is available regarding the interspecies and ontogenic differences in the receptors’ expression and signalling pathway functionality in pathological conditions, including hypoxia and shock. It could be challenged whether the comparison by Rasmussen et al. was appropriate given the healthy physiological condition of piglets, but most pharmacokinetic studies use healthy animals. The differences in pharmacokinetics could be affected if dopamine was administered in an appropriate piglet model of hypotension or shock. Further research should also aim to understand the contributing factors of high drug clearance in piglets, including the functionality of the metabolising enzymes in pathological conditions, including monoamine oxidase and catechol-O-methyl-transferase in dopamine metabolism and cytochrome P450 in general hepatic drug metabolism. Furthermore, there is limited comparative information on the drug delivery and clearance that depends on the plasma level of binding proteins, such as monoamine transporters in dopamine and alpha1-acid glycoprotein and regional blood flows. What have we learned? Animal in vivo experiments remain a primary tool to test the effects, safety, dose selection and effectiveness of pharmacological interventions at the preclinical stage. The findings provide important information on the nonclinical safety evaluation of medicinal products for paediatric use 2. However, this may not reflect the real responses, as the translation of laboratory findings to the clinical arena requires great caution. Firstly, this is related to the physiological, biochemical and pharmacological differences between animals and humans and, secondly, the pathophysiological pharmacological differences between health and disease. In neonatal research, the gap in translation is as wide as the gaps related to the animal model, the feto-neonatal transition and ontogenic development. This study did not receive any specific funding. The author has no conflict of interests to declare.

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