Mechanistic models for protein binding and transport in organ impairment


   Faculty of Biology, Medicine and Health

  , ,  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

When evaluating impact of disease on drug response, measurement of total drug concentration is typically used as surrogate for free drug concentration and pharmacological effect. However, for highly plasma-protein bound drugs (either to albumin or alpha-acid glycoprotein (AGP)), fraction unbound in plasma (fu) often differs in severe organ impairment compared with healthy volunteers/ typical patients. Current methods for predicting fu in organ impairment, such as those implemented within physiologically based pharmacokinetic (PBPK) models, consider only the changes in albumin protein concentration, while assuming that the binding affinity of drugs for albumin (Kd) is identical between healthy and organ impairment subjects. Experimental data have shown that this assumption is invalid in chronic kidney disease, because of factors such as post-translational modification of albumin and the interplay with uremic solutes that accumulate in organ impairment (e.g., indoxyl sulfate). These changes in albumin binding may also affect the transporter-mediated uptake of drugs in the liver and kidney, and consequently affect drug elimination.

The PhD student will perform extensive in vitro assays to experimentally test how the Kd assumption is violated, and the subsequent impact on drug transport. An expanded binding model that incorporates disease-related changes in Kd and albumin-mediated transporter uptake will be developed using the in vitro data generated in the project and evaluated using available clinical data. The research will primarily focus on albumin-binding in chronic kidney disease, with intention that developed methods may be implemented for AGP-binding drugs as well as hepatic impairment.

The research team has published extensively on mechanistic models for prediction of renal clearance in health and disease and has a strong track record in PBPK modelling. The PhD student will benefit from relevant training (e.g., MSc Model-based drug development), and an excellent research environment within the Centre for Applied Pharmacokinetic Research.

 Entry Requirements

Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related area/subject. Candidates with previous laboratory experience are particularly encouraged to apply.

How To Apply

For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor. On the online application form select the appropriate subject title.

For international students, we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences.

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/”

Chemistry (6) Medicine (26)

Funding Notes

Applications are invited from self-funded students. This project has a Band 2 fee. Details of our different fee bands can be found on our website View Website

References

1. Scotcher D, Galetin A. PBPK Simulation-Based Evaluation of Ganciclovir Crystalluria Risk Factors: Effect of Renal Impairment, Old Age, and Low Fluid Intake. AAPS J. 2021; 14;24(1):13.
2. Tan ML, Zhao P, Zhang L, Ho YF, Varma MV, Neuhoff S, Nolin TD, Galetin A, Huang SM. Use of Physiologically Based Pharmacokinetic Modeling to Evaluate the Effect of Chronic Kidney Disease on the Disposition of Hepatic CYP 2C8 and OATP 1B Drug Substrates. Clin Pharmacol Ther. 2019;105(3):719-729.
3. van der Made TK, Fedecostante M, Scotcher D, Rostami-Hodjegan A, Sastre Toraño J, Middel I, Koster AS, Gerritsen KG, Jankowski V, Jankowski J, Hoenderop JG, Masereeuw R and Galetin A. Quantitative translation of microfluidic transporter in vitro data to in vivo reveals impaired albumin-facilitated indoxyl sulfate secretion in chronic kidney disease. Mol Pharm. 2019; 16(11), 4551-62.
4. US Food and Drug Administration (2020). Guidance for Industry: Pharmacokinetics in Patients with Impaired Renal Function – Study Design, Data Analysis, and Impact on Dosing [DRAFT GUIDANCE]. Silver Spring, MD. https://www.fda.gov/media/78573/download

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