TABLE 2

Summary of nomenclature and methods used by regulatory agencies to calculate the unbound maximum hepatic inlet concentration of an orally administered drug

AgencyAbbreviated Terms for Total and Unbound Hepatic Inlet ConcentrationMatrixBasic Equation for Calculating Total and Unbound Hepatic Inlet Concentrationa,bEquation in Text
FDAIin,max, Iin,max,uPlasmaTotal plasma Iin,max = systemic Cmax in plasma + portal Cmax in plasmaEq. 5
Plasma Iin,max,u = plasma Iin,max × fuP
EMA[I]inlet,max, [I]u,inlet,maxBloodTotal blood [I]inlet,max = systemic Cmax in blood + portal Cmax in bloodEq. 12
Blood [I]u,inlet,max = blood [I]inlet,max × fuB
PMDAIinlet,max, Iinlet,max,uTotal blood Iinlet,max = systemic Cmax in blood + portal Cmax in blood
Blood Iinlet,max,u = blood Iinlet,max × fuB
  • EMA, European Medicines Agency; FDA, US Food and Drug Administration; PMDA, Pharmaceutical and Medical Devices Agency.

  • a fup and fuB are the fraction of unbound drug in plasma and blood, respectively.

  • b The only difference between the EMA and PMDA equations is the abbreviated terms used for the total/unbound maximum hepatic inlet concentration.