Response to Physiologically Based Pharmacokinetic Model for Prediction of Leflunomide and Teriflunomide: Should Consideration Be Given to Cannalicular Efflux Transporters?

To the Editor:

We thank Dr Srinivas for the thought‐provoking comments and the opportunity to clarify a number of aspects of our work.

With reference to Figure 2 from RUN8, the residual error model has been weighted by the inverse square root of the number of patients within each study so as to prioritize the impact of studies with higher subject numbers. For example, although the studies that included multiple sclerosis individuals were repeat dose studies (concentrations were therefore higher and the inherent variability was represented across time), given the larger subject numbers, the curve fits were equal or better to those seen with the shorter single‐dose studies. Despite this, the effect of poly‐pharmacy and varying disease states on teriflunomide concentrations should be explored further, particularly for known inducers or inhibitors of ABCG2, CYP1A2, or CYP2C19.