TABLE 5

In vitro evaluation of inhibition of efflux transporters by verinurad and metabolites M1 and M8

TransporterIC50 (μM)Imax/IC50Iu,max/IC50
P-gp
 VerinuradNI
 M1NI
 M8NI
BCRP
 VerinuradNI
 M11450.002870.000228
 M8>300
(33.8% inhibition at 300 μM)
<0.00136<0.000460
 Verinurad + M1 + M8b<0.00423<0.00069
BSEPa
 Verinurad1090.002180.0000642
MRP2a
 M11.130.3680.0295
 M85.500.07440.0251
 M1 + M8b0.4420.0546
MRP4a
 M1>10
(38.3% inhibition at 10 μM)
<0.0416<0.00333
 M8>10
(22.4% inhibition at 10 μM)
<0.0409<0.0138
 M1 + M8b<0.0825<0.0172
  • Cmax, maximum observed concentration; EMA, European Medicines Agency; FDA, Food and Drug Administration; Imax, total maximum plasma inhibitor concentration; Iu,max, maximum free plasma inhibitor concentration; NI, no inhibition.

  • a Estimated margin in analogy to efflux transporter inhibition concept in US FDA 2020 and EMA guidance, 10-fold total Cmax (US FDA): R = Imax/IC50 ≥ 0.1; 50-fold unbound Cmax (EMA): Iu,max/IC50 ≥ 0.02.

  • b The combined inhibitory potential of verinurad and its metabolites was calculated as a sum of the individual ratios of exposure in relation to in vitro inhibition constants.