title: The Complexities of Interpreting Reversible Elevated Serum Creatinine Levels in Drug Development: Does a Correlation with Inhibition of Renal Transporters Exist?
abstract: In humans, creatinine is formed by a multistep process in liver and muscle and eliminated via the kidney by a combination of glomerular filtration and active transport. Based on current evidence, creatinine can be taken up into renal proximal tubule cells by the basolaterally localized organic cation transporter 2 (OCT2) and the organic anion transporter 2, and effluxed into the urine by the apically localized multidrug and toxin extrusion protein 1 (MATE1) and MATE2K. Drug-induced elevation of serum creatinine (SCr) and/or reduced creatinine renal clearance is routinely used as a marker for acute kidney injury. Interpretation of elevated SCr can be complex, because such increases can be reversible and explained by inhibition of renal transporters involved in active secretion of creatinine or other secondary factors, such as diet and disease state. Distinction between these possibilities is important from a drug development perspective, as increases in SCr can result in the termination of otherwise efficacious drug candidates. In this review, we discuss the challenges associated with using creatinine as a marker for kidney damage. Furthermore, to evaluate whether reversible changes in SCr can be predicted prospectively based on in vitro transporter inhibition data, an in-depth in vitro-in vivo correlation (IVIVC) analysis was conducted for 16 drugs with in-house and literature in vitro transporter inhibition data for OCT2, MATE1, and MATE2K, as well as total and unbound maximum plasma concentration (Cmax and Cmax,u) data measured in the clinic.
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism (X.C., K.B., G.H.C., R.E.), and Global Regulatory Affairs, Oncology, Immunology, Biologics & Devices (I.N.), Merck Sharp & Dohme Corporation, Kenilworth, New Jersey xiaoyan_chu@merck.com.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Chu
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism (X.C., K.B., G.H.C., R.E.), and Global Regulatory Affairs, Oncology, Immunology, Biologics & Devices (I.N.), Merck Sharp & Dohme Corporation, Kenilworth, New Jersey.
authors.forename: Kelly
authors.initials: K
authors.lastname: Bleasby
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism (X.C., K.B., G.H.C., R.E.), and Global Regulatory Affairs, Oncology, Immunology, Biologics & Devices (I.N.), Merck Sharp & Dohme Corporation, Kenilworth, New Jersey.
authors.forename: Grace Hoyee
authors.initials: GH
authors.lastname: Chan
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism (X.C., K.B., G.H.C., R.E.), and Global Regulatory Affairs, Oncology, Immunology, Biologics & Devices (I.N.), Merck Sharp & Dohme Corporation, Kenilworth, New Jersey.
authors.forename: Irene
authors.initials: I
authors.lastname: Nunes
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism (X.C., K.B., G.H.C., R.E.), and Global Regulatory Affairs, Oncology, Immunology, Biologics & Devices (I.N.), Merck Sharp & Dohme Corporation, Kenilworth, New Jersey.
authors.forename: Raymond
authors.initials: R
authors.lastname: Evers
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D003404:Creatinine / Q000097:blood*; D015195:Drug Design; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D007677:Kidney Function Tests; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000075102:Organic Cation Transporter 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D015415:Biomarkers; D029362:Organic Anion Transporters, Sodium-Independent; D000075102:Organic Cation Transporter 2; C491013:SLC22A2 protein, human; C490280:SLC22A7 protein, human; D003404:Creatinine