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(MRC DTP) Model-driven optimization of drug therapy and individualisation of healthcare in chronic kidney disease


Project Description

Chronic kidney disease (CKD) is associated with increasing age, as approximately 50% of individuals over 75 years are affected by some degree of kidney disease. The ageing population is also more likely to have common comorbidities (cardiovascular diseases, diabetes) and be prescribed multiple medications, and hence the risk of potential drug-drug interactions (DDI) in patients with renal impairment is high. However, high percentage of drug product labels lack any evidence-based recommendations for dosage adjustment in patients with advanced renal impairment. Therefore, CKD patients are susceptible to adverse side effects of drugs (e.g., drug induced kidney injury) and increased risk of inappropriate dosing. Model-based precision dosing is an approach for determining suitable dose adjustments using in silico tools (e.g., physiologically-based pharmacokinetic (PBPK) models) to improve drug efficacy and safety in specific populations such as CKD.

This project aims to develop quantitative translational tools to facilitate individualized healthcare in CKD and provide guidance to clinicians for rational dose adjustment when direct evidence in this patient population is lacking.
CKD patients exhibit impaired active tubular secretion and therefore reduced renal excretion mediated via renal transporters. PBPK modelling in this project will implement different disease-related perturbations of active secretion and focus on selected renal transporter probes with reported nephrotoxicity/clinical data in patients with advanced CKD. The modelling and simulation will be supported by in vitro studies where activity of selected renal transporters (e.g., OAT1) will be investigated under different experimental conditions mimicking CKD. Uptake of selected drugs (same as used for modelling purposes) in proximal tubule cells will be investigated with cells exposed to plasma from healthy and subjects with severe CKD (to be obtained from collaborator Prof. Philip Kalra, Salford Royal Hospital, Manchester). Functional transporter studies will be supported by LC-MS proteomic measurements of the transporter expression in different experimental conditions and related to protein expression in vivo.

The successful applicant will receive state-of-the-art training to build a broad and transferable skillset including in vitro cellular assays, proteomics analysis and PBPK modelling. Active participation in the Centre for Applied Pharmacokinetic Research (CAPKR), University of Manchester will provide opportunity to interact with a multi-disciplinary research team. Student will be encouraged to attend international conferences to promote work and build network as an independent researcher, as well as publish in highly-cited peer reviewed journals. The proposed inter-disciplinary and model-driven approach has strong foundations and builds upon previous and ongoing research in CAPKR.

Weblink for Dr Aleksandra Galetin
https://www.research.manchester.ac.uk/portal/aleksandra.galetin.html

Weblink for Dr Daniel Scotcher
https://www.research.manchester.ac.uk/portal/daniel.scotcher.html

Centre for Applied Pharmacokinetic Research, University of Manchester
https://www.capkr.manchester.ac.uk/

Entry Requirements:
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Funding Notes

This project is to be funded under the MRC Doctoral Training Partnership. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the MRC DTP website View Website

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

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