Validation of a total IC₅₀ method which enables in vitro assessment of transporter inhibition under semi-physiological conditions

Abstract

1. Accurate predictions of clinical transporter-mediated drug–drug interactions (DDI) from in vitro data can be challenging when compounds have poor solubility and/or high nonspecific binding. Additionally, current DDI predictions for compounds with high plasma–protein binding assume that the unbound fraction in plasma is 0.01, if the experimental value is less than 0.01 or cannot be determined. This approach may result in an overestimation of DDI risk. To overcome these challenges, it may be beneficial to conduct inhibition studies under physiologically relevant conditions.

2. Here, IC₅₀ values, determined in the presence of 4% bovine serum albumin approximating human plasma albumin concentrations, were successfully used to predict DDI for uptake transporters, OATP1B1/1B3, OCT1/2, OAT1/3 and MATE1/2K.

3. The IC₅₀ values of reference inhibitors with 4% bovine serum albumin, considered total IC₅₀, were comparable to the predicted values based on nominal IC₅₀ values determined under protein-free conditions and unbound fraction in plasma. Calculation of R-total and C_max/IC_50,total values using total plasma exposure and total IC₅₀ values explained the clinical DDI or absence of it for these inhibitors.

4. These results suggest that IC₅₀ determinations in the presence of 4% albumin can be used, in the context of clinical total exposure, to predict DDI involving uptake transporters.

Keywords:

• Albumin
• DDI
• drug–drug interactions
• transporters
• total IC₅₀ values

Acknowledgements

The authors are thankful to J. Cory Kalvass and Ganesh Rajaraman for their review of the manuscript. The authors also thank Jun Sun and Clare Gerstein for their technical assistance.

Declaration of interest

This manuscript was sponsored by AbbVie. AbbVie contributed to the design, research, and interpretation of data, writing, reviewing, and approving the publication. Ryota Kikuchi, Vincent C. Peterkin, William J. Chiou, Sonia M. de Morais, and Daniel A.J. Bow are employees of AbbVie.

Supplementary material available online