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

clinical pharmacology and therapeutics

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