Identification of Appropriate Endogenous Biomarker for Risk Assessment of Multidrug and Toxin Extrusion...

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 N¹ -methylnicotinamide (1-NMN)), N¹ -methyladenosine (m¹ A) was included as novel biomarkers. 1-NMN and m¹ 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 m¹ A). It is concluded that 1-NMN and m¹ A CL_r can be leveraged as quantitative MATE1/2-K biomarkers for DDI risk assessment in healthy volunteers.