The Centre for Applied Pharmacokinetic Research (CAPKR) provides an international lead in the development, evaluation and implementation of in vitro and in silico approaches for predicting human pharmacokinetics. Pharmacokinetics plays a pivotal role in drug discovery, development and use since it widely recognised that being bioactive is not enough to ensure therapeutic success. Knowledge on how a drug enters and is processed by the body is as critical as knowledge as its interaction with target sites. Even today many promising drug candidates fail to make it through drug development due to poor pharmacokinetic properties such as inadequate absorption, poor stability, excessive interaction with other drugs. Other drugs are prematurely withdrawn from the market due to toxicities arising from pharmacokinetic idiosyncrasies.
CAPKR’s aim is to improve prediction at all steps between drug discovery and use with mechanism-based modelling methodologies. Major advances have been made in delineating the science that underpins the development and evaluation of paradigms for human prediction. Research activities include, prediction of drug hepatic clearance, molecular and kinetic basis of drug-drug interactions, pharmacokinetic and statistical modelling. Our use of human tissue, and validated surrogates such as recombinant proteins together with computer simulation and modelling are in sympathy with the current ethical and political pressures to reduce, refine and replace the use of animals in research.
Prediction of Drug Clearance in Humans
Drug metabolism and pharmacokinetics (DMPK) play a pivotal role in drug discovery, development and use. Often drug development is halted or use limited by poor PK properties, mainly drug clearance. We are developing paradigms for the quantitative prediction of human drug clearance through the comprehensive use of different in vitro systems to delineate interactions between the cytochrome P450 and UDP-glucuronyltransferase enzymes and other cellular processes (including permeability and transporter proteins). We are particularly interested in the the need to incorporate variability and uncertainty within the extrapolation process and transporter-mediated events in delineating hepatic clearance.
Molecular and kinetic basis of Drug-Drug Interactions
In the era of polypharmacy, drug-drug interactions (DDIs) are of major concern and continue to result in drugs being within drawn from the commercial market. We are interested in inhibition of CYP enzymes transporter proteins as the major cause of drug-drug interactions and the ability of simple in vitro systems to predict this effect. We are assessing the modelling of time dependent inhibition, multiple DDIs, transporter involvement and enzyme induction effects due to drug treatment and chemical environmental exposure.