Pharmacokinetics plays a vital component in the drug discovery and development process, and provides critical and quantitative knowledge on how a drug enters and is processed by the body. Pharmacokinetics aims to quantify and improve prediction at all steps between drug discovery and use with mechanism-based modelling methodologies.
Our goal is to provide guidance in the development, evaluation and implementation of in vitro and in silico approaches for predicting and improving human clinical pharmacokinetics to optimise dosing and pharmacodynamic response.
Research strands actively pursued include:
CNS targetting and drug delivery
We are developing, assessing and evaluating the use of in-vitro organtypic cell culture models to assess both blood-brain barrier (BBB) and blood-CSF-barrier (BCSFB) drug targetting and delivery to the brain. We are actively working with immortalised and primary cell culture systems to charaterise the disposition of drugs across the brain and CSF and the factors that influence this.
Whole Body Physiologically-Based Pharmacokinetic Modelling
We are developing, assessing and evaluating the use of whole body physiologically-based pharmacokinetic (PBPK) models to the prediction of drug pharmacokinetic behavior, utilising drug specific physicochemical, in vitro and nonclinical data along with extensive physiological data. Key to this approach is the development of modular organ/tissue specific models.
Key successes have developed human predictive pharmacokinetics models to assess the extent of oral drug absorption and central nervous systems drug disposition (brain parenchyma cells and cerebrospinal fluid) using a limited set of pre-clinical drug specific parameters. These approaches are currently being applied to the development of predictive pharmacokinetics models of other human tissues/organs including the placenta, breast tissue, nasal cavity, bone and eye.
In-vitro and in-vivo microdialysis
We are developing novel in-vitro and in-vivo microdialysis probes and methodologies for quantifying temporal drug concentrations in peripheral tissues and organs for use in conjunction with in-silico pharmacokinetic modeling approaches. The usefulness of microdialysis as a method to identify and assess pharmacodynamic (biomarker) responses is also underway within our laboratory and will be used to further enhance existing pharmacokinetic modeling approaches.
Systems biology and bioinformatics: Drug transporter modelling
To ensure successful drug-based treatment strategies, favorable pharmacokinetic characteristics of drug absorption, distribution, metabolism and excretion are essential. By modulating these processes we are able to influence the efficacy of disease treatments.
Drug-efflux transporters located within the plasma membrane, which actively extrude agents out of cells, have recently been identified as key mechanisms which have the potential to alter pharmacokinetic properties and are involved in the phenomenon of cancer multidrug resistance.
Research within the group aims to apply bioinformatics approaches to predicting the structure (homology modelling) of pharmacokinetically relevant drug transporter proteins such as P-glycoprotein (P-gp), Breast Cancer Resistance Protein (BCRP) and Multidrug Resistance Protein-1 (MRP-1), and suitable candidate modulators (ligand-docking) of drug-transporters proteins.