TABLE 1

List of the parameter values for the bosentan PBPK model incorporating target binding

The table lists the values for the rank 1 parameter set (with the smallest SSR value of 2.21) and the minimum and maximum values among the entire 401 parameter sets with the SSR values less than 2.30 (from the ranks 1 to 401)

Estimated valuesInitial range
ParameterUnitRank 1(Min, max)(Lower, upper)
Optimized
 Kdμmol/l0.0110(0.0103, 0.0122)(0.00003, 0.3)
 koff/h0.610(0.524, 0.659)(0.004, 40)
 XTotalRμmol27.1(25.7, 28.9)(0.08, 800)
 Vcentrall10.9(10.6, 11.2)(0.05, 500)
 PSdif,infl/h5.87(5.25, 7.28)(0.1, 1000)
 Km,act,infμmol/l0.713(0.678, 0.741)(0.02, 200)
 Vmax,act,infμmol/h1380(1290, 1590)(30, 300,000)
 CLmetl/h11.8(11.5, 12.5)(0.1, 1000)
 ka/h1.28(1.23, 1.36)(0.01, 100)
 PSent,b,effl/h1.27(1.18, 1.37)(7 × 10−7, 7 × 10−3)
Secondary
 konl/μmol per hour55.4(44.9, 61.3)
β0.328(0.292, 0.349)
 CLint,alll/h639(628, 645)
  • β, a hybrid parameter to determine the rate-determining step in the hepatic elimination; CLint,all, an overall intrinsic clearance of the liver; CLmet, hepatic metabolic clearance; ka, the absorption rate constant; Vmax,act,inf, the maximum velocity for the active influx through the basolateral membrane of hepatocytes; PSdif,inf, the influx intrinsic clearance via passive diffusion through the sinusoidal membrane of hepatocytes; PSent,b,eff, the efflux intrinsic clearance via passive diffusion through the basolateral membrane of enterocytes; Vcentral, the volume of the central compartment. Secondary parameters (kon, β, and CLint,all) were calculated using the following equations: kon = koff/Kd; β = CLmet/(CLmet + PSdif,eff); CLint,all = (PSdif,inf + Vmax,act,inf/Km,act,inf) × β, where PSdif,eff is the efflux intrinsic clearance via passive diffusion through the sinusoidal membrane of hepatocytes.