Pallabi Mitra , Boehringer Ingelheim, Ridgefield, CT
Lalitha Podila , Boehringer Ingelheim, Ridgefield, CT
Meeghan Michalewicz , Boehringer Ingelheim, Ridgefield, CT
Mitchell E Taub , Boehringer Ingelheim, Ridgefield, CT
Objective: Creatinine is commonly used as a biomarker of renal function in clinical trials, as changes in serum creatinine or creatinine clearance are thought to indicate the potential for renal toxicity. However, in vivo changes in creatinine can also be due to inhibition of renal transporters, since creatinine is a substrate of multiple renal transporters, including but not limited to OCT2. In vitro, substrate dependent inhibition of OCT2 has been observed; however, this hasn’t been systematically studied for the OCT2 substrates most commonly used in industry to develop an in vitro/in vivo Correlation (IVIVC). Methods: Radiolabeled creatinine and metformin were utilized as OCT2 substrates. Inhibition of active uptake of these substrates was evaluated in HEK293 cells transiently transfected with OCT2. Nine compounds, all of which are known to produce reversible changes in serum creatinine without affecting GFR, were evaluated as OCT2 inhibitors. IVIVCs were evaluated in terms of true positives (TP), true negatives (TN), false positives (FP), and false negatives (FN). The in vitro cutoff value employed was Cmax,u/IC50 0.1 (FDA guideline). In vivo cutoff values employed were ≥ 15% increase in serum creatinine and ≥ 25% increase in AUC of metformin. Results: When creatinine was used as the in vitro OCT2 substrate, the % of correct predictions (TPs and TNs) were 78% and 88% for creatinine and metformin IVIVCs, respectively. When metformin was used as the in vitro OCT2 substrate, the % of correct predictions (TPs and TNs) were 14% and 29 % for creatinine and metformin IVIVCs, respectively. With creatinine, TPs were 63-67%; using metformin, TPs did not occur. These results were primarily driven by all tested compounds being more potent inhibitors of creatinine than metformin. Conclusions: The predictive ability of exposure changes in creatinine or metformin solely due to OCT2 inhibition depended on the in vitro substrate of OCT2 used. Compared to metformin, which is a commonly used in vitro probe substrate of OCT2, creatinine was much more predictive of clinically relevant changes in creatinine exposure.