P211 Evaluation of Renal Transporter Inhibition Using Creatinine and NMN (N1-Methylnicotinamide) as Substrates In Vitro to Assess the Clinical Risk of Elevated Serum Creatinine and Renal DDIs

Sumathy Mathialagan , Pharmacokinetics, Dynamics & Metabolism, Pfizer Inc., Groton, CT
Bo Feng , Pdm, Pfizer Global Research & Development, Groton, CT
Evaluation of Renal Transporter Inhibition Using Creatinine and NMN (N1-Methylnicotinamide) as Substrates In Vitro to Assess the Clinical Risk of Elevated Serum Creatinine and Renal DDIs

Sumathy Mathialagan, A. David Rodrigues, and Bo Feng

Pharmacokinetics, Dynamics & Metabolism, Medicine Design, Pfizer Inc., Groton CT

Creatinine (Cr) is a widely accepted biomarker for renal toxicity, but its renal clearance via active secretion (transporter-mediated) is significant (~30%). For a given new chemical entity, therefore, elevations in serum creatinine (SCr) may be caused by the inhibition of one or more renal transporters without renal toxicity. In the present study, an effort was made to assess the correlation between the inhibition of renal transporters in vitro and elevations in SCr. A total of 15 model compounds were chosen based on their known effect on SCr and minimal impact on glomerular filtration rate (GFR). For the first time, their inhibition potencies against four known creatinine renal transporters (organic cation transporter 2 [OCT2], organic anion transporter 2 [OAT2], and two forms of multidrug and toxin extrusion [MATE1 and MATE2K]) were assessed using creatinine as a probe substrate. Collectively, the data suggest that the observed elevations in SCr can be attributed to the inhibition of one or more renal transporter(s), but inhibition of renal transporters does not necessarily lead to elevated SCr. Thus, renal transporter inhibition data can be used (retrospectively) to rationalize SCr changes. With supportive scholarship, we have successfully rationalized SCr elevations (portfolio compounds A & B) based on in vitro renal transporter inhibition data. On the other hand, it has been widely observed that the simple thresholds proposed by regulatory agencies are conservative and give rise to a ~30% false positive rate. Therefore, it is very important to validate sensitive biomarkers for renal OCT2/MATE1/MATE2K (e.g., N1-methylnicotinamide, NMN) in the hope of supporting renal transporter DDI risk assessment for portfolio compounds in Phase I. Use of NMN, in conjunction with improved markers for GFR (e.g., Cystatin C), could be leveraged to facilitate the assessment of transporter inhibition dose dependency (SAD study) and time course (MAD study); the results would be combined with in vitro transporter inhibition data to support modeling exercises, develop an integrated package for agency review, and possibly discharge risk without having to conduct a formal probe drug interaction study. Given the potential for substrate-dependent inhibition of transporters, comparison of in vitro IC50 values across multiple OCT2/MATE substrates (e.g., Cr, NMN and metformin) is warranted.