Table 2.
Comparison of all investigated base models
| LCL | TVARCL | MMCL | MMCL + LCL | MMCL + TVARCL | LCL + 0.EL | |
|---|---|---|---|---|---|---|
| LCL, L/h (RSE%) | 0.0222 (3) | 0.0262 (3) | ‐ | 0.0153 (4) | 0.0174 (5) | 0.0206 (‐) |
| V 1, L (RSE%) | 3.84 (3) | 3.67 (3) | 3.75 (3) | 3.71 (2) | 3.65 (3) | 3.82 (‐) |
| Q, L/h (RSE%) | 0.0188 (17) | 0.0282 (12) | 0.0332 (19) | 0.0323 (4) | 0.0368 (5) | 0.0216 (‐) |
| V 2, L (RSE%) | 3.38 (12) | 1.65 (11) | 2.67 (8) | 3.25 (6) | 2.65 (4) | 3.31 (‐) |
| K M, mg/L (RSE%) | ‐ | ‐ | 283 (26) | 9.81 (5) | 13.3 (21) | ‐ |
| V max, mg/h (RSE%) | ‐ | ‐ | 9.48 (17) | 0.882 (5) | 0.861 (5) | ‐ |
| I max, % (RSE%) | ‐ | –19.6 (16) | ‐ | ‐ | –23.1 (20) | ‐ |
| T 50, weeks (RSE%) | ‐ | 7.26 (15) | ‐ | ‐ | 20.5 (29) | ‐ |
| γ (RSE%) | ‐ | 2.54 (24) | ‐ | ‐ | 1 FIX | ‐ |
| K0, mg/h (RSE%) | ‐ | ‐ | ‐ | ‐ | ‐ | 0.0472 (‐) |
|
η LCL, CV% (RSE%) [Shr%] |
38.3 (6) [6] |
36.6 (6) [6] |
‐ |
37.9 (8) [19] |
36.1 (23) [23] |
39.4 (‐) [8] |
|
η V1, CV% (RSE%) [Shr%] |
26.8 (11) [31] |
27.3 (10) [31] |
26.4 (15) [32] |
25.9 (11) [32] |
26.2 (10) [32] |
27.4 (‐) [32] |
|
η V2, CV% (RSE%) [Shr%] |
103.9 (13) [27] |
84.1 (9) [39] |
83.4 (17) [29] |
61.2 (9) [27] |
61.3 (14) [32] |
104.4 (‐) [29] |
|
η Vmax, CV% (RSE%) [Shr%] |
‐ | ‐ |
30.5 (9) [6] |
43.6 (10) [34] |
48.8 (12) [12] |
‐ |
|
η Tmax, CV% (RSE%) [Shr%] |
‐ |
25.2 (11) [29] |
‐ | ‐ |
51.5 (18) [35] |
‐ |
|
η K0, CV% (RSE%) [Shr%] |
‐ | ‐ | ‐ | ‐ | ‐ |
150.3 (‐) [57] |
| Additive RUV, mg/L (RSE%) | 9.44 (11) | 7.79 (12) | 8.14 (13) | 5.85 (12) | 4.85 (22) | 8.65 (‐) |
| Proportional RUV, CV% (RSE%) | 23.1 (5) | 22.8 (4) | 23.4 (5) | 24.0 (4) | 23.5 (4) | 22.9 (‐) |
| AIC (SAEM‐IMP) | –6132 | –6990 | –6534 | –6947 | –7324 | –5990 |
0.EL, zero‐order elimination; AIC, Akaike information criterion; I max, maximum change in time‐varying clearance; K 0, zero‐order rate constant of elimination from central compartment; K M, Michaelis‐Menten rate constant; LCL, linear clearance; MMCL, Michaelis‐Menten clearance; η, between‐patient variability; Q, intercompartmental exchange rate; RSE, relative standard error; RUV, residual unexplained variability; Shr, shrinkage; T 50, time at which clearance is halved; TVARCL, time‐varying linear clearance; V 1, central volume of distribution; V 2, peripheral volume of distribution; V max, maximum rate of saturable elimination; γ, curve shape factor.
The model exhibiting the best performance comprised parallel Michaelis–Menten and time‐varying linear clearance (MMCL + TVARCL).