Fitted Parameters | Definition | mPBPK(TM)-PD | mPBPK(SFM)-PD | Full PBPK(TM)-PD | Full PBPK(SFM)-PD |
---|---|---|---|---|---|
fQ | Fraction of intestinal flow to enterocyte region | 1 | 0.114 (2.26) | 1 | 0.105 (0.533) |
fd | Fraction of cardiac output to peripheral compartment | 0.0021 (0.021) | 0.0032 (0.025) | 0.0035 (0.002) | 0.0048 (0.001) |
ka (h−1) | Absorption rate constant of 1,25(OH)2D3 | 1.43 (0.011) | 1.26 (0.013) | 1.50 (0.004) | 1.61 (0.0021) |
kdeg (h−1) | Degradation rate constant of 1,25(OH)2D3 in lumen | 0.0042 (6.06) | 0.0013 (11.6) | 0.0017 (2.34) | 0.0012 (6.65) |
Kperi or Kothers | Partition coefficient of peripheral/other compartment | 0.117 (0.025) | 0.161 (0.032) | 0.272 (0.003) | 0.335 (0.003) |
Rsyn (fmol × h−1) | Endogenous synthesis rate of 1,25(OH)2D3 | 50.9 (0.26) | 23.0 (0.238) | 31.0 (0.247) | 21.5 (0.116) |
Turnover rate constants of renal Cyp27b1 | — | — | 0.220 (11.5) | 0.245 (9.72) | |
(h−1) | |||||
Hill coefficient for indirect response of renal Cyp27b1 function | — | — | 3.57 (14.0) | 2.71 (12.1) | |
(mL×h−1)a | Hepatic metabolic intrinsic clearance of 1,25(OH)2D3 via hepatic Cyp24a1 | 0.031 (0.841) | 0.0782(2.82) | 0.0043 (1.78) | 0.0010 (3.03) |
(mL×h−1)a | Intestinal metabolic intrinsic clearance of 1,25(OH)2D3 via intestinal Cyp24a1 | 0.229 (0.348) | 0.220 (0.196) | 0.0011 (0.038) | 0.0014 (0.412) |
(mL×h−1)a | Renal metabolic intrinsic clearance of 1,25(OH)2D3 via renal Cyp24a1 | 0.053 (0.435) | 0.0641 (0.782) | 0.0242 (0.008) | 0.0280 (0.0066) |
(mL×h−1)a | Brain metabolic intrinsic clearance of 1,25(OH)2D3 via brain Cyp24a1 | 0.030 (15.0) | 0.0345 (3.37) | 0.0006 (8.30) | 0.0003 (0.412) |
Hill coefficient for indirect response function of hepatic Cyp24a1 | — | — | 1.24 (2.45) | 1.75 (0.020) | |
Hill coefficient for indirect response function of renal Cyp24a1 | — | — | 2.64 (0.665) | 3.59 (0.081) | |
Hill coefficient for indirect response function of intestinal Cyp24a1 | — | — | 0.985 (1.22) | 2.09 (0.002) | |
Hill coefficient for indirect response function of brain Cyp24a1 | — | — | 0.878 (0.148) | 0.576 (0.076) | |
or (h−1) | Turnover rate constant of hepatic Cyp24a1 | 0.0413 (0.052) | 0.044 (0.708) | 0.045 (0.006) | 0.047 (0.008) |
or (h−1) | Turnover rate constant of intestinal Cyp24a1 | 0.218 (0.278) | 0.174 (0.485) | 0.489 (0.005) | 0.287 (0.067) |
or (h−1) | Turnover rate constant of renal Cyp24a1 | 0.0256 (0.038) | 0.0238 (0.026) | 0.012 (0.065) | 0.047 (0.008) |
or (h−1) | Turnover rate constant of brain Cyp24a1 | 1.20 (2.73) | 2.10 (4.52) | 1.28 (0.051) | 1.87 (5.10) |
Power coefficient on renal Cyp24a1 enzyme turnover | 0.931 (0.112) | 0.766 (0.933) | — | — | |
Power coefficient on hepatic Cyp24a1 enzyme turnover | 1.27 (0.120) | 1.33 (0.056) | — | — | |
Power coefficient on brain Cyp24a1 enzyme turnover | 0.804 (0.389) | 0.800 (0.498) | — | — | |
Power coefficient on intestinal Cyp24a1 enzyme turnover | 1.40 (0.116) | 1.42 (0.160) | — | — | |
HK | Power coefficient on renal intrinsic clearance | 0.828 (0.0622) | 0.784 (0.0372) | — | — |
HL | Power coefficient on hepatic intrinsic clearance | 1.86 (0.0769) | 0.470 (2.23) | — | — |
HBr | Power coefficient on brain intrinsic clearance | 0.142 (17.8) | 0.374 (5.68) | — | — |
HI | Power coefficient on intestinal intrinsic clearance | 0.230 (0.246) | 0.054 (7.82) | — | — |
AIC | Akaike information criteria | 9367 | 9270 | 10,006 | 9993 |
WSSR | Weighted sum of squared residuals | 1684 | 1644 | 1664 | 1478 |
dfb | Degrees of freedom | 989 | 988 | 986 | 985 |
F valuec | (critical F = 3.84) | Calculated F score | 24.0d versus mPBPK(TM)-PD | 5.93d versus mPBPK(TM)-PD | 55.3d versus mPBPK(SFM)-PD |
124d versus PBPK(TM)-PD |
↵a Fitted CLint,met,T values were adjusted by corresponding unbound fraction of 1,25(OH)2D3 in tissue (fT).
↵b Degrees of freedom are the number of data points (n = 1010) used in the model minus the number of parameters being fitted.
↵c F score was calculated using , where dfj > dfi.
↵d F score suggests a significant improvement in goodness of fit (critical F = 3.84) (Boxenbaum et al., 1974); the rank order of goodness of fit (from poorest to best for optimal fit): mPBPK(TM)-PD < mPBPK(SFM)-PD < full PBPK(TM)-PD < full PBPK(SFM)-PD model.