TABLE 1

Total (bound + unbound) and unbound maximum hepatic inlet concentration in plasma (the FDA approach) and blood (the EMA and PMDA approach) for drugs with different Rb values

Simulated comparisons were made for drugs A, B, and C with an Rb of 0.5, 1.0, and 2.0, respectively. The oral dose of each drug was 325 µmol. Each drug had a total (bound + unbound) systemic plasma Cmax of 4.0 µM, and each was 80% bound to plasma protein (fuP = 0.2). In each case, Fa ⋅ Fg was 1, and ka was 0.1 min−1. Hepatic blood flow (QH) was 1.62 l/min.

DrugRbTotal Systemic CmaxTotal Portal CmaxTotal Maximum Hepatic Inlet Concentration (Iin,max)Fraction UnboundUnbound Maximum Hepatic Inlet Concentration (Iin,max,u)
PlasmaaBloodbPlasmacBlooddPlasmaeBloodfPlasmagBloodhPlasmaiBloodj
μMμMμMμMμMμMfuPfuBμMμM
A0.542402044220.20.48.88.8
B1.044202024240.20.24.84.8
C2.048102014280.20.12.82.8
FDA (based on drug concentrations in plasma)
A0.5440440.28.8
B1.0420240.24.8
C2.0410140.22.8
EMA and PMDA (based on drug concentrations in blood)
A0.5220220.48.8
B1.0420240.24.8
C2.0820280.12.8
• EMA, European Medicines Agency; FDA, US Food and Drug Administration; PMDA, Pharmaceutical and Medical Devices Agency; Rb, Ratio of drug concentration in blood (CB) to drug concentration in plasma (CP).

• a The total drug concentration in systemic plasma is determined experimentally. It was set to 4 µM for drugs A–C.

• b Calculated as follows:

• c Calculated as follows:

• d Calculated as follows:

• e Calculated as follows:

• f Calculated as follows:

• g The unbound concentration of drug in plasma (fuP) is determined experimentally. It was set to 0.2 for Drugs A–C.

• h Calculated as follows:

• i Calculated as follows:

• j Calculated as follows: