Fig. 3.

Schematic representation of the population-pharmacokinetic whole-blood concentration (WBC) model for tacrolimus. The central compartment, with volume V1, is swiftly in equilibrium with the peripheral compartment represented by volume V2. Drug transfer between this peripheral compartment and the central compartment is described with the inter-compartmental clearance parameter Q. k_a is the absorption rate constant and CL is the whole-blood tacrolimus clearance. The unbound plasma concentration of tacrolimus (UPC) was computed using a non-linear model, as follows: UPC = (WBC × kd1)/(Bmax × Ht − WBC), where kd1 is the dissociation constant (fitted parameter), Bmax is the maximum binding capacity (fitted parameter), and Ht is the observed hematocrit (last observation carried forward). The total plasma concentration (TPC) was computed using a linear model, as follows: TPC Nplasma × UPC with Nplasma non-specific binding constant for total plasma concentrations (fitted parameter)