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Modelling and Simulation to Support Qualification of Endogenous Transporter Biomarkers: Current Stat
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Modelling and Simulation to Support Qualification of Endogenous Transporter Biomarkers: Current Stat

 Export to Your Calendar 10/21/2020
When: October 21, 2020
11:00 AM ET
Where: Online Webinar


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In recent years, there has been an increasing interest to identify, characterize, and qualify endogenous biomarkers as clinically relevant tools for the evaluation of transporter function in vivo. Such biomarkers can provide an early indication of potential transporter-mediated interactions and inform the need for subsequent studies with clinical transporter probes. Unlike clinical probes, interpretation of endogenous biomarker interaction data needs to consider factors such as biomarker synthesis/formation and/or impact of diurnal rhythm. 

The webinar will discuss the utility of monitoring single vs. combination of biomarkers in early identification of transporter-mediated interaction risk. Application of mechanistic modelling and simulation to support qualification of endogenous biomarkers will be shown, focusing on coproporphyrin I (CPI) and creatinine as examples. Minimal physiologically-based pharmacokinetic (PBPK) model for CPI that incorporates the impact of organic anion transporting polypeptides (OATP)1B1 c.521T>C polymorphism and sex on CPI plasma exposure and inter-individual variability in its baseline concentration will be presented. Importance of mechanistic biomarker models as translational tools to facilitate the design of clinical studies and evaluation of transporter-mediated interactions will be discussed.

Creatinine is widely used as a biomarker of glomerular filtration, and renal function. Inhibition of renal transporters involved in its active secretion causes transient serum creatinine elevation, which can be mistaken as impaired renal function. The webinar will present mechanistic
models of creatinine within physiologically-based framework accounting for multiple transporters involved in creatinine renal elimination, assuming either unidirectional or bidirectional-OCT2 transport (driven by electrochemical gradient). Robustness of creatinine model was assessed by predicting creatinine-drug interactions with 10 perpetrators with different inhibitory effect on renal transporters. The physiological basis of the creatinine model represents the most advanced framework for evaluating interplay between multiple processes in creatinine renal disposition. Ability to extend this dynamic model to specific populations (e.g., subjects with impaired renal function) and corresponding evaluation of transporter-mediated interaction risk in this patient cohort will be illustrated.


This webinar will be presented by Aleksandra Galetin. 

 

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