Table 4.
Final estimates of population PK-PD parameters
| Parameter | Description | Estimate | %RSE | Bootstrap median (95% CI)a |
|---|---|---|---|---|
|
Pharmacokinetics | ||||
| CL/F (L/h) |
Apparent clearance |
12.2 |
7.39 |
12.5 (4.9~14.9) |
| V/F (L) |
Apparent volume of distribution |
691 |
6.54 |
712 (324~980) |
| D2 (h) |
Duration of zero-order absorption |
20.2 |
7.08 |
19.9 (16.6~23.0) |
| KA (h-1) |
Absorption rate constant of first-order absorption |
0.00653 |
16.23 |
0.00721 (0.0010~0.1715) |
| ALAG (h) |
Lag time to the initiation of first-order absorption |
85.7 |
3.92 |
88.1 (80.9~108.0) |
| RFb |
Alternate variable for relative fraction absorbed in zero-order absorption process |
0.185 |
55.68 |
0.24 (-1.17~0.94) |
| ωCL (%) |
Between subject variability of CL |
26.1 |
35.1 |
24.5 (14.4~32.7) |
| ωV (%) |
Between subject variability of V |
23.8 |
58.0 |
23.7 (0.4~37.6) |
| ωD2 (%) |
Between subject variability of D2 |
35.7 |
27.1 |
34.8 (23.0~49.4) |
| ωRF (%) |
Between subject variability of RF |
34.7 |
64.1 |
32.1 (0.3~54.2) |
| ωka (%) |
Between subject variability of KA |
77.0 |
37.1 |
59.5 (0.7~95.4) |
| σadd (pg/mL) |
Additive error |
3.92 |
12.65 |
3.83 (-3.36~4.80) |
| σprop (%) |
Proportional error |
7.8 |
26.06 |
7.0 (-8.8~11.9) |
|
Pharmacodynamics | ||||
| BASE (nmol/L) |
Baseline of neopterin |
5.85 |
4.17 |
5.88 (5.39~6.34) |
| KOUT (h-1) |
First-order elimination rate of serum neopterin |
0.0311 |
17.20 |
0.03 (0.02~0.04) |
| EMAX |
Maximum stimulatory effect |
16.1 |
53.19 |
17.45 (7.06~62.42) |
| GA |
Hill coefficient (γ) |
1.24 |
11.85 |
1.27 (1.01~2.52) |
| CAc |
Coefficient |
405 |
115.80 |
616.5 (27~13115) |
| CBc |
Coefficient |
0.0068 |
27.73 |
0.0064 (0.0014~0.0119) |
| ECBc |
Baseline of EC50 |
2.17 |
152.07 |
1.66 (0.05~74.67) |
| MTT (h) |
Mean transit time |
14.6 |
11.37 |
14.5 (9.82~19.2) |
| ωBASE (%) |
Between subject variability of BASE |
13.85 |
51.84 |
12.63 (3.91~20.79) |
| ωCB (%) |
Between subject variability of CB |
57.31 |
43.31 |
46.21 (0.32~72.61) |
| ωGA (%) |
Between subject variability of GA |
13.51 |
55.80 |
13 (0.32~36.49) |
| ωECB (%) |
Between subject variability of ECB |
21.31 |
172.97 |
21.39 (0.45~55.86) |
| ωMTT (%) |
Between subject variability of MTT |
13.36 |
94.92 |
10.75 (0.55~24.21) |
| σadd (nmol/L) | Additive error | 1.14 | 11.05 | 1.11 (0.95~1.37) |
a95% CIs obtained from estimation of 1000 bootstrap-resampled datasets; bFraction absorbed in zero-order absorption, Fz = eRF/(1+ eRF); Fraction absorbed in first-order absorption: 1-Fz; cEC50 =ECB*(1+CA*(1-e-CB*Time)); RSE Relative standard error.