In Vitro Assessment of the Drug-Drug Interaction Potential of Verinurad and Its Metabolites as Substrates and Inhibitors of Metabolizing Enzymes and Drug Transporters

Abstract

Verinurad is a selective uric acid transporter 1 (URAT1) inhibitor in development for the treatment of chronic kidney disease and heart failure. In humans, two major acyl glucuronide metabolites have been identified: direct glucuronide M1 and N-oxide glucuronide M8. Using in vitro systems recommended by regulatory agencies, we evaluated the interactions of verinurad, M1, and M8 with major drug-metabolizing enzymes and transporters and the potential for clinically relevant drug-drug interactions (DDIs). The IC₅₀ for inhibition of CYP2C8, CYP2C9, and CYP3A4/5 for verinurad was ≥14.5 µM, and maximum free plasma concentration (I_u,max)/IC₅₀ was <0.02 at the anticipated therapeutic C_max and therefore not considered a DDI risk. Verinurad was not an inducer of CYP1A2, CYP2B6, or CYP3A4/5. Verinurad was identified as a substrate of the hepatic uptake transporter organic anion-transporting polypeptide (OATP) 1B3. Since verinurad hepatic uptake involved both active and passive transport, there is a low risk of clinically relevant DDIs with OATP, and further study is warranted. Verinurad was a substrate of the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), and renal transporter organic anion transporter 1 (OAT1), although it is not considered a DDI risk in vivo because of dose-proportional pharmacokinetics (P-gp and BCRP) and limited renal excretion of verinurad (OAT1). M1 and M8 were substrates of multidrug resistance-associated protein (MRP) 2 and MRP4 and inhibitors of MRP2. Apart from verinurad being a substrate of OATP1B3 in vitro, the potential for clinically relevant DDIs involving verinurad and its metabolites as victims or perpetrators of metabolizing enzymes or drug transporters is considered low. SIGNIFICANCE STATEMENT: Drug transporters and metabolizing enzymes have an important role in the absorption and disposition of a drug and its metabolites. Using in vitro systems recommended by regulatory agencies, we determined that, apart from verinurad being a substrate of organic anion-transporting polypeptide 1B3, the potential for clinically relevant drug-drug interactions involving verinurad and its metabolites M1 and M8 as victims or perpetrators of metabolizing enzymes or drug transporters is considered low.