P-gp inhibition interactions, in vitro to in vivo translation

PerpetratorIn Vitro SubstrateIC50Dose [I]1a[I]1/IC50[I]2b[I]2/IC50In Vivo VictimAUC RatioReference
TrametinibDigoxin5.520.040.00711.52.09(FDA, 2013p)
VilanterolDigoxin>1000.0254.4 × 10−44.4 × 10−6c(FDA, 2013b,d)
CanagliflozinDigoxin19.330010.50.54d2645137c,dDigoxin1.2(FDA, 2013k)
SimeprevirPaclitaxel85.920014.50.169c,d106612.4c,dDigoxin1.4(FDA, 2013r)
VortioxetineN/S4.4100.047<0.1 (0.01c)10523.9c,dN/T(FDA, 2013e)
IbrutinibN/S4.95600.28<0.1 (0.06c)5085>10 (1038c,d)N/T(FDA, 2013j)
AfatinibDigoxin3.4f400.0780.023g329.397c,dN/T(FDA, 2013i)
  • N/T, not tested in NDA reviews; N/S, not specified.

  • a Mean steady-state total (free and bound) Cmax after administration of the highest proposed clinical dose.

  • b Intestinal exposure, dose (in mol)/250 ml.

  • c Value computed by the DIDB Editorial Team.

  • d Underlined values exceed FDA cut-off to warrant in vivo study, 0.1 for [I]1/IC50, 10 for [I]2/IC50.

  • e Clinical study ongoing at time of NDA submission therefore final result not available.

  • f Ki value.

  • g [I]/Ki.