Extrapolating pharmacokinetic models from adults to neonates and infants: Case studies with paracetamol

The absorption, distribution, metabolism and excretion (ADME) of drugs in the human body may be quite different between adults and infants/neonates, since the enzymes involved in metabolic pathways exhibit distinct levels of activities at different ages. In the case of paracetamol, for example, neonates have a lower total clearance per kg bodyweight compared with adults, with proportionally higher sulfation, lower glucuronidation and oxidation. However, the very limited available data on the exact contributions of the different pathways require computational strategies for extrapolating pharmacokinetic models from adults to neonates/infants. In this talk I will introduce our in silico models for such a practice, and to gain more insights in the contributions of the different metabolic pathways. The model was a two-compartment model, i.e. the blood and urine, with initial data adopted from adult patients receiving dental extraction operations. Then the model parameters were recalibrated per the data from a children’s hospital. We used (a) nonlinear regressional analysis; (b) Latin Hypercube Sampling analysis to analyse the parameters and their interactions. We show that the model could reproduce some typical drug ADME profiles in very young children. The in silico strategy may also be applicable to other age-related extrapolations of PK models.

hwe001

  • University of Auckland, New Zealand
Dr Ho received PhD in Bioengineering from the University of Auckland in 2011. His research interests include mathematical modelling for physiological flows, physiologically based pharmacokinetics modelling, 3D visualisation of bio-structures, medical image computing and surgical simulations. He is the first or corresponding author of ~40 peer-reviewed international journal papers/book chapters, including the top journals in his research field.