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.
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 behaviour, 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. Current projects include:
Regional CNS pharmacokinetic model development
Special population pharmacokinetics (Geriatrics)
Middle/inner ear pharmacokinetic model development
Systems biology and bioinformatics: Drug transporter modelling
To ensure successful drug-based treatment strategies, favourable 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.
CNS targeting 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 targeting and delivery to the brain. We are actively working with immortalised and primary cell culture systems to characterise the disposition of drugs across the brain and CSF and the factors that influence this. Current projects include:
Assessing drug transporter (ABCG2) expression and modulation at CNS barriers
Nasal targeting and by-passing the blood-brain barrier
In parallel to approaches to deliver drug across the BBB, we are actively engaged in exploiting the olfactory pathways to allow direct ‘nose-to-brain’ drug delivery. Our research is focussed on the design of appropriate nasal delivery systems which will increase nasal residency but also provide an element of olfactory mucosa targeting. Our work focusses on both intelligent biopolymer systems and exploiting existing pMDI inhaler technologies for olfactory targeting. Current projects include:
Formulation of intelligent ‘responsive’ hydrogel carrier systems
Nasal cavity deposition studies using nasal cast methods
Nasal pMDI development for olfactory deposition
Otic (ear) drug delivery systems
In a cross-discipline initiative, we are working closely with our colleagues in the Audiology to develop patient-appropriate drug delivery system which will non-invasively deliver appropriate small and large molecular weight therapeutics to patients in a controlled manner using existing cochlear technologies. Current project include:
Development drug and biologic loaded cochlear electrode and electrode coating
Development of ‘triggered’ cochlear drug delivery electrodes