TABLE 7

In vitro evaluation of inhibition of human hepatic uptake transporters by verinurad and metabolites M1 and M8

TransporterIC50 (μM)Iin,max (μM)aIu,in,max/KibRc
OATP1B1
 Verinurad19.47.890.02331.023
 M13.070.6940.03221.032
 M819.80.6820.02071.021
 Verinurad + M1 + M8d0.07621.076
OATP1B3
 Verinurad31.07.890.003651.004
 M118.40.6940.003021.003
 M8>100
(40.6% inhibition at
100 μM)
0.682<0.00230<1.002
 Verinurad + M1 + M8d<0.00897<1.009
OAT2
 Verinurad>100
(33.1% inhibition at 100 μM)
7.89<0.00453<1.005
OCT1
 VerinuradNI
 M1NI
 M8NI
  • Cmax, maximum observed concentration; FDA, Food and Drug Administration; fu, unbound fraction in plasma; Iin,max, maximum hepatic inlet concentration; Imax, total maximum plasma inhibitor concentration; Iu,in,max, maximum free hepatic inlet concentration; Ki, inhibitory constant; NC, not calculated.

  • a Iin,max calculated based on US FDA 2020 guidance. Iin,max = Imax + (Fa × Fg × Ka × dose/(Qh)/(B:P) = 0.238 µM + [(1 × 1 × 0.1 × 68.9 mmol/1.5/0.6 = 7.654] = 7.89, in which dose = 24 mg = 68.9 µmol, Qh = 1.5 l/min, and B:P = 0.6. For metabolites, Iin,max is estimated from total Cmax and Rb of 0.6–0.693 µM and 0.682 µM for M1 and M8, respectively.

  • b Ki was estimated to equal IC50 when substrate concentration was well below the reported Km or as IC50/2 when substrate concentration was close to Km.

  • c R = 1 + ((fu × Iin,max)/IC50) ≥ 1.1.

  • d 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.