For many marketed drugs, including those eliminated by non-renal routes, exclusion of chronic kidney disease (CKD) patients from pivotal clinical trials has caused a lack of dose adjustment guidance in product labels for these patients. Such lack of information exacerbates other challenges in safely administering drugs to CKD patients, including their older age, underlying vulnerability to adverse side effects of drugs, comorbidities and prevalence of polypharmacy.
Physiologically-based pharmacokinetic (PBPK) modelling is an in silico approach supported by regulatory agencies and pharmaceutical industry to inform drug development and precision dosing. Recent US FDA guidance1 highlights PBPK simulation-based early evaluation of changes in drug exposure in patients with impaired renal function, thus enabling inclusion of CKD patients in late-phase clinical trials. When suitable clinical data are not forthcoming, PBPK simulations have the potential to provide evidence-based dose adjustment guidance in CKD patients. However, despite promising applications of PBPK modelling to improve drug safety and efficacy through precision dosing2,3, wider application of CKD virtual populations, including consideration of drug-drug interaction effects is still immature.
This project aims to develop quantitative translational tool to facilitate individualized healthcare in CKD patients and provide guidance to clinicians for rational dose adjustment when direct evidence in this specific patient population is lacking. This will ensure that the right patient gets the right treatment at the right dose.
Chronic kidney disease-related alterations in functional activity of hepatic drug metabolising enzymes and transporters will be investigated using advanced in vitro cellular systems under conditions mimicking severe CKD. Metabolism and/or transport rates of selected clinically relevant drugs will be investigated in long term cultured human hepatocytes, with cells exposed to plasma from healthy subjects and severe CKD patients. Further experiments will be undertaken to improve mechanistic understanding of altered plasma protein binding of drugs in disease condition, and impact of CKD on drug-drug interactions. Integration of pathophysiological changes, functional enzyme/transporter activities, and/or quantitative proteomic expression data, will result in robust CKD-PBPK model to be applied as a precision dosing tool.
The successful applicant will receive state-of-the-art training and build transferable skillset including in vitro cellular assays, proteomics and PBPK modelling. Active participation in the Centre for Applied Pharmacokinetic Research (CAPKR), University of Manchester will provide excellent opportunity to interact with a multi-disciplinary research team, build networks and publish in highly-cited peer reviewed journals. The proposed inter-disciplinary and model-driven approach has strong foundations and builds upon previous and ongoing CAPKR research2-4.
https://www.research.manchester.ac.uk/portal/aleksandra.galetin.html
https://www.research.manchester.ac.uk/portal/daniel.scotcher.html
https://www.capkr.manchester.ac.uk/
Entry Requirements
Applicants must have obtained or be about to obtain a First or Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in an appropriate area of science, engineering or technology.
How to Apply
To be considered for this project you MUST submit a formal online application form - full details on how to apply can be found on the MRC Doctoral Training Partnership (DTP) website www.manchester.ac.uk/mrcdtpstudentships
Applicants interested in this project should make direct contact with the Primary Supervisor to arrange to discuss the project further as soon as possible.
Equality, Diversity and Inclusion
Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/
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