Coming full circle: The potential utility of real-world evidence to discern predictions from a physiologically based pharmacokinetic model

Today real word data (RWD) are playing a greater role in informing health care decisions. A physiologically based pharmacokinetic model (PBPK) and observed exposure–risk relationship predicted an increased bleeding risk induced by rivaroxaban (RXB) in patients with mild to moderate chronic kidney disease (CKD) taking concomitant medications that are combined Pgp-CYP3A inhibitors. In this commentary, we explore the potential use of RWD to assess the clinical consequence of this complex drug–drug interaction predicted from PBPK. This is a retrospective, case control, pilot study using a RWD dataset of 896,728 patients with mild to moderate chronic kidney disease and rivaroxaban use that was refined based upon combined Pgp-CYP3A inhibitor exposure and report of drug-induced bleeding (DIB). The odds ratio of patients with mild to moderate chronic kidney disease taking rivaroxaban with or without concurrent Pgp-CYP3A inhibitor use having a DIB was calculated. The odds ratio for DIB was 2.04 (CI₉₅ 1.82, 2.3; p < 0.001) suggesting an approximate doubling of bleeding risk which is consistent with the rivaroxaban exposure changes predicted by the published PBPK model and observed exposure–risk relationship. This exploratory analysis demonstrated the potential utility of RWD to assess model-based predictions as part of a drugs life cycle management.