Identification of Appropriate Endogenous Biomarker for Risk Assessment of Multidrug and Toxin Extrusion Protein‐Mediated Drug‐Drug Interactions in Healthy Volunteers

• DOI: 10.1002/cpt.2022
• Publication Date: 2020-08-31T18:20:00Z
• Authors: Takeshi Miyake; Emi Kimoto; Lina Luo; Sumathy Mathialagan; Lauren M. Horlbogen; Ragu Ramanathan; Linda S. Wood; Jillian G. Johnson; Vu H. Le; Manoli Vourvahis; A. David Rodrigues; Chieko Muto; Kenichi Furihata; Yuichi Sugiyama; Hiroyuki Kusuhara
• Keywords: Adult; Male; 0301 basic medicine; Cross-Over Studies; Organic Cation Transport Proteins; Research; Kidney; Risk Assessment; Healthy Volunteers; Metformin; Cell Line; 3. Good health; Young Adult; 03 medical and health sciences; HEK293 Cells; Pyrimethamine; Asian People; Creatinine; Humans; Hypoglycemic Agents; Drug Interactions; Biomarkers

Endogenous biomarkers are emerging to advance clinical drug‐drug interaction (DDI) risk assessment in drug development. Twelve healthy subjects received a multidrug and toxin exclusion protein (MATE) inhibitor (pyrimethamine, 10, 25, 75 mg) crossover fashion identify an appropriate endogenous biomarker assess MATE1/2‐K‐mediated DDI the kidneys. Metformin (500 was also given as reference probe for MATE1/2‐K. In addition previously reported candidates (creatinine N 1 ‐methylnicotinamide (1‐NMN)), ‐methyladenosine (m A) included novel biomarkers. 1‐NMN m A presented superior MATE1/2‐K since changes their renal clearance (CL r ) along with pyrimethamine dose were well‐correlated metformin CL changes. The of creatinine reduced by pyrimethamine, however, its poorly correlated Nonlinear regression analysis vs. mean total concentration plasma) yielded estimate inhibition constant ( K i fraction pathway sensitive pyrimethamine. vivo value thus obtained further converted unbound Ki using plasma which comparable vitro MATE1 (1‐NMN) MATE2‐K (1‐NMN A). It is concluded that can be leveraged quantitative volunteers.