The Ontogeny of UDP-glucuronosyltransferase Enzymes, Recommendations for Future Profiling Studies and Application Through Physiologically Based Pharmacokinetic Modelling

Limited understanding of drug pharmacokinetics in children is one of the major challenges in paediatric drug development. This is most critical in neonates and infants owing to rapid changes in physiological functions, especially in the activity of drug-metabolising enzymes. Paediatric physiologically based pharmacokinetic models that integrate ontogeny functions for cytochrome P450 enzymes have aided our understanding of drug exposure in children, including those under the age of 2 years. Paediatric physiologically based pharmacokinetic models have consequently been recognised by the European Medicines Agency and the US Food and Drug Administration as innovative tools in paediatric drug development and regulatory decision making. However, little is currently known about age-related changes in UDP-glucuronosyltransferase-mediated metabolism, which represents the most important conjugation reaction for xenobiotics. Therefore, the objective of the review was to conduct a thorough literature survey to summarise our current understanding of age-related changes in UDP-glucuronosyltransferases as well as associated clinical and experimental sources of variance. Our findings indicate that there are distinct differences in UDP-glucuronosyltransferase expression and activity between isoforms for different age groups. In addition, there is substantial variability between individuals and laboratories reported for human liver microsomes, which results in part from a lack of standardised experimental conditions. Therefore, we provide a number of best practice recommendations for experimental conditions, which ultimately may help improve the quality of data used for quantitative clinical pharmacology approaches, and thus for safe and effective pharmacotherapy in children

Pediatric Pharmacokinetics and Dose Predictions: A Report of a Satellite Meeting to the 10th Juvenile Toxicity Symposium

On April 24, 2019, a symposium on Pediatric Pharmacokinetics and Dose Predictions was held as a satellite meeting to the 10th Juvenile Toxicity Symposium. This symposium brought together scientists from academia, industry, and clinical research organizations with the aim to update each other on the current knowledge on pediatric drug development. Through more knowledge on specific ontogeny profiles of drug metabolism and transporter proteins, integrated into physiologically-based pharmacokinetic (PBPK) models, we have gained a more integrated understanding of age-related differences in pharmacokinetics (PKs), Relevant examples were presented during the meeting. PBPK may be considered the gold standard for pediatric PK prediction, but still it is important to know that simpler methods, such as allometry, allometry combined with maturation function, functions based on the elimination pathway, or linear models, also perform well, depending on the age range or the mechanisms involved. Knowledge from different methods and information sources should be combined (e.g., microdosing can reveal early read-out of age-related differences in exposure), and such results can be a value to verify models. To further establish best practices for dose setting in pediatrics, more in vitro and in vivo research is needed on aspects such as age-related changes in the exposure-response relationship and the impact of disease on PK. New information coupled with the refining of model-based drug development approaches will allow faster targeting of intended age groups and allow more efficient design of pediatric clinical trials.Pharmacolog

Pediatric pharmacokinetics and dose predictions: a report of a satellite meeting to the 10th Juvenile Toxicity Symposium

On the 24th of April 2019 a symposium on Pediatric pharmacokinetics and dose predictions was held as a satellite meeting to the 10th Juvenile Toxicity Symposium. The aim of this meeting was to bring together scientists from academia, industry and clinical research organizations to update each other on the current knowledge on pediatric drug development. The increased knowledge on specific ontogeny profiles of drug metabolism and transporter proteins, integrated into physiologically based pharmacokinetic (PBPK) models has allowed a more integrated understanding of age-related differences in PK, for which examples were given during the meeting. PBPK may be considered the gold-standard for pediatric PK prediction, but still it is important to know that simpler methods like allometry, allometry combined with maturation function, functions based on the elimination pathway or linear models also perform well depending on the age range or the mechanisms involved. It is important to combine knowledge from different methods and information sources; e.g. techniques like microdosing can gain early read-out of age-related differences in exposure and in addition such results can be value to verify models. To further establish best practices for dose setting in pediatrics more in vitro and in vivo research is needed on such aspects as age related changes in the exposure response relationship and also the impact of disease on PK. New information coupled with the refining of model based drug development approaches will allow faster targeting of intended age groups and allow more efficient design of pediatric clinical trials