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Precision dosing strategies require accounting for between-patient variability in pharmacokinetics. To that end, significant progress has been made in identifying and evaluating endogenous biomarkers of transporter function, with a particular focus on the assessment of transporter drug-drug interactions and investigation of disease-related changes in transporter function.1-4 Recently, tissue-derived plasma exosomes (liquid biopsy) have emerged as a novel tool to quantify changes in expression of enzymes and transporters.5 However, existing studies are generally done in Caucasian population and understanding of any inter-ethnic differences is limited.
This PhD project, in collaboration with Peking University Third Hospital (Prof. Dongyang Liu, Clinical Pharmacology and Pharmacometric Office), will investigate the use of transporter/enzyme biomarker data in different patient populations (e.g., renal impairment, patients with old age) to create corresponding virtual twin physiologically-based pharmacokinetic (PBPK) models. Interethnic differences and changes in transporter/enzyme activities in Chinese populations will also be investigated. Main goal is to leverage clinical biomarker and drug probe data from multiple patient groups to support model-informed precision dosing in those patient cohorts.
The student will:
– Investigate effect of inflammation/disease on different enzymes and transporters (e.g. CYP3A4, OATs, OATP1B) at functional level in specific patient populations using biomarker data
– Create virtual twin PBPK models and population PK models (if necessary) for selected drugs and for specific patient populations using biomarker data to support precision dosing
– Disseminate work through peer-reviewed publications and scientific meetings
Funding Notes
References
2. Takita H et al, (2022). Coproporphyrin I as an Endogenous Biomarker to Detect Reduced OATP1B Activity and Shift in Elimination Route in Chronic Kidney Disease. Clin Pharmacol Ther. 112(3):615-626.
3. Chu X et al, (2018). Clinical Probes and Endogenous Biomarkers as Substrates for Transporter Drug-Drug Interaction Evaluation: Perspectives From the International Transporter Consortium. Clin Pharmacol Ther. 104(5):836-864.
4. Chu X. et al (2022) Modeling in Specific Populations: An ITC Perspective. Clin Pharmacol Ther. 2022 Sep;112(3):501-526.
5. Achour B et al, (2021). Liquid Biopsy Enables Quantification of the Abundance and Interindividual Variability of Hepatic Enzymes and Transporters. Clin Pharmacol Ther. 109(1):222-232).
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