Table 4.
Summary of estimated parameters and relative standard error (RSE %) from four different methods evaluating datasets with data below the limit of detection (BLOD)
| Method description | Method 1 BLOD = discard | Method 5 = final modelBLOD = 1/2LOD | Method 6 1st BLOD = 1/2LOD, others discarded | Method 4 BLOD = censored, −2LL function |
|---|---|---|---|---|
| Parameter | Mean (RSE %) | Mean (RSE %) | Mean (RSE %) | Mean |
| Pharmacokinetic parameters | ||||
| Clp (l h−1) | 23.2 (20.3) | 31.5 (14.0) | 30.7 (11.5) | 29.8 |
| Vc (l) | 74.3 (42.7) | 56.7 (33.9) | 72.4 (28.7) | 132 |
| ka cap (h−1) | 0.021 (21.9) | 0.032 (46.7) | 0.041 (38.0) | 0.029 |
| ka sol (h−1) | 0.132 (30.5) | 0.125 (44.2) | 0.138 (31.3) | 0.168 |
| Frel | 1.61 (19.1) | 0.817 (23.5) | 0.722 (21.3) | 0.751 |
| Q | 83.3 (20.9) | 71.3 (35.3) | 79.9 (20.7) | 71.3c |
| Vper | 2660 (25.3) | 2090 (35.0) | 1610 (25.3) | 2090c |
| CLm (l h−1) | 14.9 (20.1) | 18.3 (12.9) | 18.0 (10.6) | 15.4 |
| Vm (l) | 3.98 (45.5) | 2.67 (49.8) | 2.83 (42.4) | 4.75 |
| tlag (min) | 18.3 (2.66) | 19.3 (1.68) | 17.7 (1.93) | 17.4 |
| Between-subject variability (CV %) | ||||
| BSV Clp | 49.6 (83.3) | 22.1 (75.2) | 15.6 (94.3) | 26.6 |
| BSV Vc | 96.0 (64.1) | 77.3 (48.5) | 67.9 (51.1) | 183.0 |
| BSV ka cap | 62.4 (54.1) | 91.9 (33.5) | 102.0 (28.3) | 66.6 |
| BSV ka sol | 126.9 (25.3) | 106.3 (31.4) | 110.5 (47.7) | 90.6 |
| BSV Frel | 37.9 (53.3) | 62.3 (24.7) | 63.2 (28.3) | 40.1 |
| Residual variability (CV %) | ||||
| Proportional error | ||||
| Itraconazole | 30.2 (27.5) | 40.8 (16.6) | 45.0 (12.7) | 83.2 |
| Hydroxy-itraconazole | 34.0 (11.9) | 47.9 (12.7) | 46.8 (12.9) | 33.7 |
| Additive error | ||||
| Itraconazole | 0.0084 | |||
| Hydroxy-itraconazole | 0.0511 | |||
c, Fixed; −2LL, −2 Loglikelihood; Clp, clearance of parent drug (itraconazole); Vc, volume of distribution of the central compartment for itraconazole; ka cap, absorption rate for capsules; ka sol, absorption rate for solution; Frel, relative bioavailability; Q, intercompartment clearance; Vper, volume of distribution of peripheral compartment for itraconazole; CLm, clearance for hydroxy-itraconazole; Vm, volume for hydroxy-itraconazole; tlag, lag-time; BSV, between-subject variability.