Director, Clinical Pharmacology & Discovery Medicine at GSK
Associate Professor at Leiden/Amsterdam Center for Drug Research
Honorary Lecturer at University College London
Dr Della Pasqua was appointed to the Division of Pharmacology in May 2001. He received his PhD from Leiden University in 1998 on the thesis "Prer-clinical Pharmacokinetic-Pharmacodynamic Modelling of the Anticonvulsant Effect" (Professors M. Danhof and D.D. Breimer) and subsequently joined GlaxoSmithKline in the UK in the Division of Clinical Pharmacology and Discovery Medicine. Dr Della Pasqua is leading on Modelling and Simulations aspect of the WP, working with Sven van Dijkman, Msc, PhD student at Leiden/Amsterdam Center for Drug Research. Here is a summary of their work so far. To attain the goals of the GRiP consortium, epilepsy was chosen as an exemplar disease, because patients may benefit greatly from the application of innovative methods and results can be evaluated in a rather straightforward manner. With GRiP, the assessment of efficacy is central in this issue as the current guidelines and general research do not consider whether endpoints are sensitive enough to pharmacological activity. This leads to problems in both therapeutic use of anti-epileptic drugs and in the discovery and development of novel compounds.
Lack of sensitivity of an endpoint and absence of relevant biomarkers of the pharmacological effect make it impossible to define dose rationale and decide if the patient is treated optimally to suppress and/or treat the disease or symptoms. Given that the use of model-based approaches has been accurately describe treatment effects and outcome. It is anticipated that disease evolves over time, leading to phenomena such as tolerance and refractoriness, all of which can be parameterised as disease-specific parameters. This approach would facilitate the characterisation of drug properties independently from the underlying changes due to disease progression as well as from the changes in pharmacokinetics due to developmental growth. The availability of such a model-based approach will provide the basis for clinical protocol optimisation, including better patient stratification and dose regimens.
First, a systematic review of the current knowledge and use of modelling in epilepsy and its gaps is being written. Using this information studies will be planned to address the gaps in available models for disease course, dose-exposure relationships and treatment efficacy assessment. The resulting integrated models will be used to more accurately assess the effect of treatment on the disease course and/or the expression of symptoms. When the model performs well, it will be used to make predictions across different subpopulations such as from children to adults and between different drug types, seizure types and aetiologies. The possibility of using historical data as prior information to optimise treatment and study designs will also be assessed. Finally, a review of the currently available biomarkers and any possible improvement in that field will be written to make it possible to more accurately describe changes in disease and from there to more accurately describe treatment effects.
By applying these steps in the case of paediatric epilepsy it will be shown how modelling and simulations are useful tools for understanding diseases, finding or developing more sensitive biomarkers, using historical data to make extrapolations and optimise treatment selections and trial designs. This information can then be used to make recommendations on the development of workshops and other educational tools that other work packages will use and recommendations on the use of these methods in clinical paediatric medicine and pharmacology.