TABLE 2

Equations for risk assessments/margin calculations for transporter and enzyme inhibition as described by the EMA (2013), US FDA (2020), or JPMDA (2018)

Transporters/OrganVerinuradM1 and M8
P-gp, BCRP in gastrointestinal tractIgut/IC50 or Ki ≥ 10 (oral) (all regulatory agencies)Not applicable to metabolites
P-gp, BCRP in liver and kidneyImax/IC50 ≥ 0.1 (US FDA)
Iu,max/IC50 ≥ 0.02 (EMA)
Imax/IC50 ≥ 0.1 (US FDA)
Iu,max/IC50 ≥ 0.02 (EMA)
OATP1B1, OATP1B3 in liverIu,in,max/IC50 or Ki ≥ 0.1 (considering first-pass concentration) (US FDA, JPMDA)
Iu,in,max/IC50 ≥ 0.04 (EMA)
Iu,max/IC50 or Ki ≥ 0.1 (considering systemic blood concentration) (US FDA, JPMDA)
Iu,max/IC50 ≥ 0.04 (EMA)
OAT1, OAT3, OCT2, MATE1, MATE2-K in kidneyIu,max/IC50 or Ki ≥ 0.1 (US FDA, JPMDA; OATs and OCT2)
Iu,max/IC50 or Ki ≥ 0.02 (EMA, JPMDA; MATEs)
Iu,max/IC50 or Ki ≥ 0.1 (US FDA, JPMDA; OATs and OCT2)
Iu,max/IC50 or Ki ≥ 0.02 (EMA, JPMDA; MATEs)
OAT2, OCT1 in liverNo explicit guidance by regulatory agencies
Iu,in,max/IC50 or Ki ≥ 0.1 in analogy to OATP considerations (US FDA, JPMDA)
Iu,in,max/IC50 or Ki ≥ 0.04 in analogy to OATP considerations (EMA)
No explicit guidance by regulatory agencies
Iu,max/IC50 or Ki ≥ 0.1 in analogy to OATP considerations (US FDA, JPMDA)
Iu,max/IC50 or Ki ≥ 0.04 in analogy to OATP considerations (EMA)
BSEP in liver;

MRP2, MRP4 in liver and kidney
No explicit guidance by regulatory agencies
Iu,max/IC50 or Ki ≥ 0.1 in analogy to MATE considerations (US FDA)
Imax/IC50 ≥ 0.1 in analogy to P-gp and BCRP considerations (US FDA)
Iu,max/IC50 ≥ 0.02 in analogy to P-gp, BCRP, and MATE considerations (EMA, JPMDA; MATEs)
No explicit guidance by regulatory agencies
Iu,max/IC50 or Ki ≥ 0.1 in analogy to MATE considerations (US FDA)
Imax/IC50 ≥ 0.1 in analogy to P-gp and BCRP considerations (US FDA)
Iu,max/IC50 ≥ 0.02 in analogy to P-gp, BCRP, and MATE considerations (EMA, JPMDA; MATEs)
CYP3A in gastrointestinal tractIgut/Ki ≥ 10 (oral) (all regulatory agencies)Not applicable to metabolites
CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A in liverIu,max/Ki ≥ 0.02 (all regulatory agencies)Iu,max/Ki ≥ 0.02 (all regulatory agencies)
  • EMA, European Medicines Agency; FDA, Food and Drug Administration; fu, unbound fraction in plasma; Igut, intestinal luminal concentration; Imax, total maximum plasma inhibitor concentration; Iu,in,max, maximum free hepatic inlet concentration; Iu,max, maximum free plasma concentration; JPMDA, Japanese Pharmaceuticals and Medical Devices Agency; Ki, inhibitory constant.