TABLE 4

In vitro evaluation of direct inhibition of metabolizing enzymes by verinurad and metabolites M1 and M8

R. R, R1, and R1,gut calculations follow the US FDA 2020 guidance

EnzymeIC50 (μM)Iu,max/IC50RR1R1,gut
CYP1A2
 Verinurad>100
 M1>30
 M8>30
CYP2A6
 Verinurad
 M1NI
 M8>30
CYP2B6
 Verinurad>100
 M1>30
 M8>30
CYP2C8
 Verinurad14.50.000491.00049
 M1>30
 M8NI
CYP2C9
 Verinurad25.60.000281.000281.00028
 M1NI
 M8NI
CYP2C19
 Verinurad>100
 M1NI
 M8NI
CYP2D6
 Verinurad>100
 M1NI
 M8NI
CYP3A4/5
 Verinurad77.1 and 85.3a0.000091.000094.6
 M1NI
 M8NI
CYP2E1
 Verinurad
 M1NI
 M8>30
UGT1A1
 Verinurad192.7
 M1
 M8
UGT2B7
 Verinurad1120
 M1
 M8
  • Imax, total maximum plasma inhibitor concentration; NI, no inhibition.

  • a Risk assessment was based on the lowest IC50 value, which was obtained with midazolam as a substrate.