By Sid Bhoopathy
Increasing reliance on in vitro and modeling tools to predict the human pharmacological outcome of transporter interactions has raised their overall prominence. Both practitioners and regulators would ideally like these methodologies to have high translatable accuracy, reduce or eliminate the possibility of false negatives, and generate meaningful quantitative data without assay redundancy.
The spotlight thus far has primarily been on improved outcomes via protocol development tailored to unique test-compound characteristics, and selection of an optimal in vitro model. However, there is an increasing need to shift the emphasis upstream, i.e., toward the source, and to better characterize the intrinsic variability of the test system, which is the foundation for all subsequent testing steps. Evolving industry and regulatory expectations on ruggedness, establishing an a priori definition of test system assay window, reproducibility of quality control data, and so forth are resulting in development of sophisticated analytics that can provide users enhanced confidence in the data obtained from these tools. Innovative ideas have also augmented scoring transporter involvement from the traditional/basic approach of solely relying on a threshold ratio or a ratio of ratios to bespoke modeling approaches that have the ability to better predict the need for an actionable step by combining apparent drug affinity to the interacting transporter with its unbound concentration at the target site. The webinar The Role of Transporters on Unbound Intracellular Concentrations: Experimental and Modeling Considerations provides insights on guidelines for choosing appropriate in vitro testing models and utilizing their outcomes as input parameters for model development.
Achieving the expected in vitro/modeling target profile in a consistent manner still has several knowledge limitations and also requires a nuanced understanding of how expectations transition from a researcher to a prescriber or patient who is consuming information presented on the product label.
The upcoming AAPS/ITC Joint Workshop on Drug Transporters presents an excellent opportunity to learn from the experts and a forum to exchange information with other researchers in this field as we all juggle myriad expectations to evaluate and to better predict “the true effect of DDIs in real word situations” that can ultimately benefit the patient.
Which area of transporter/drug-drug interaction research should we focus on to improve translatable outcomes?