Pharmacometrics

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To facilitate pharmacometrics enhancement of the PDN, the THD funding will be used to establish an Australian Centre for Pharmacometrics (ACP), with the headquarters at the University of South Australia.  This site has been chosen on the basis of its critical mass of expertise in the field and relationship to the NCRIS supported Large Animal Imaging Facility, which can offer unique insights into drug disposition.  However, key pharmacometrics groups from across Australia and New Zealand are jointly involved in the ACP.

The role of the ACP is to facilitate training and education in pharmacometrics and increase the utilization of such analyses in biomedical research on a national scale.  It will facilitate drug development and biomedical research nationally by providing high-end computing facilities and pharmacometric expertise.

The Australian Centre for Pharmacometrics, through a modelling and simulation approach to data analysis, will aggregate:
•    In vitro and in silico modelling to provide initial basic pharmacological understanding.
•    Small and large animal studies used collectively to provide a complete pharmacological (pharmacokinetic and pharmacodynamic) understanding.
•    Pharmacometric analyses throughout the whole drug-development process to provide a mechanistic and quantitative understanding of the drug and identify characteristics of an “optimal” formulation, thus improving the efficiency of development progress, including the optimal design of the studies themselves.
•    This process is integrative and cyclical.  Information from each step is feedback and evaluated for its impact on the development cycle via pharmacometric input.

Pharmacometrics combines our knowledge base of disease with our understanding of drug pharmacology, side effects and treatment variability.  This field has often been referred to as “modelling and simulation” in the past, and can be defined as the science that coordinates all information about quantifying drugs and drug effects, the mechanistic processes involved in disease and its treatment, plus the interpreted results of in vitro, animal and clinical trials.  The combined information encourages efficient and improved drug candidate selection and formulation development via rational informed decision-making.  Given the ever increasing cost of drug development, it is important that Australia be at the forefront of “smart drug development”.  

The value of pharmacometrics is illustrated by:
•    Drug models describing relationships between exposure, response for both desired and undesired effects, and individual patient characteristics.
•    Disease models describing the relationship between biomarkers and clinical outcomes, time course of disease and placebo effects.
•    The capacity to integrate mechanistic knowledge from prior understanding, related compounds, chemistry and biology, together with the ability to include both richly sampled data and more limited/incomplete data typically unusable in traditional statistical approaches.
•    The generation of trial models describing trial design, subject numbers, sampling times, inclusion/exclusion criteria, patient discontinuation and adherence.  Trials are then designed to provide the most efficient and optimal way to answer the question being asked.
•    Improved analyses that are designed, conducted and reviewed in the context of ongoing development, therapeutic and regulatory decisions.

Recent advances in pharmacometrics provide a clear mechanism to streamline, facilitate and optimise the pre-clinical development of pharmacotherapeutic agents.  By providing a guided progression, informed by pharmacometric analyses, the conduct and design of studies will maximise the efficiency of pre-clinical development.  The result is clear and rational progress of molecules and optimal formulation for human clinical trials.  This process will increase the efficiency of the present process in Australia in which the progression is often fragmented.

Importantly it may also lead to increases in efficiency by early culling of molecules that are unlikely to be clinically useful due to a poor pharmacokinetic / pharmaceutical properties – this is presently a major impediment to drug development as it a significant cause of costly drug failures during the clinical development stages.