The objective at this stage should be to more increase the knowing in the drug properties in vivo and to extrapolate findings, identifying correlations or generating predictions about a drug?s effectiveness in humans . Juvenile toxicological research, which involve younger animals, have been made use of to investigate a drug?s pharmacology and toxicology. Findings are extrapolated assuming a correlation between developmental growth in animals and young children . Even if the assumptions and rationale is often supported for some indications, several concerns really have to be addressed to allow PD0332991 kinase inhibitor proper interpretation on the findings. In contrast, M&S can optimise the use and interpretation of those data, enabling a mechanism-based, systematic extrapolation of your data across species . Furthermore, it allows quantitative assessment of age- or growth-related differences in drug effects and consequently the potential implications for different paediatric age groups . In addition, the techniques available at this stage, such as PBPK and PBPK-PD models , can use in vitro data to predict plasma and tissue concentrations . This implies substantial reduction in the number of animals per experiment and sometimes the replacement of animals by in silico experiments.
Also in this case, the use of a model-based approach allows optimisation of experimental protocols, improving the accuracy and efficiency supplier MDV3100 kinase inhibitor of data extrapolation. In summary, the benefits from M&S methodologies at the non-clinical stage include the prediction and characterisation of primary PK parameters and pharmacodynamic properties . Model parameters can then be implemented to predict the dose range to be tested in clinical research, including the requirements for optimal sampling and study design . M&S in clinical drug development Limited availability of patients and practical constraints, such as difficulties in blood sampling, have often been used as justification for the lack of systematic evaluation of drug response in small children . M&S can address many of these limitations, but its wide implementation in clinical development has remained wishful thinking. This is partly due to the lack of knowing and working knowledge in quantitative pharmacology and pharmacometrics by spon- sors, regulatory agencies and investigators who are responsible for the planning, design and/or approval of clinical trials. PBPK and disease models The difficulties in performing paediatric trials constrain physicians in extrapolating data from the adult population to children. For this purpose, simple allometric methods based on body weight or body surface area have already been frequently made use of. However, particularly in neonates and infants, the use of the allometric approach may fail to identify the ideal dosing range . Once more PBPK models may play a pivotal role in the estimation of dosing requirements across the paediatric population.