Introduction
Methods
Erlotinib study
Study population
Study design
Sample preparation, analysis and PK calculations
PBPK modeling
Parameter | Predicted value | Optimized value |
---|---|---|
Molecular weight (g/mol) | 393.45 | 393.45 |
LogP (neutral) | 3.13 | 2.7 |
Basic pKa | 4.46 | 5.4 |
Intrinsic solubility (mg/ml) | 0.078 | 0.0089 |
Solubility at pH = 2 (mg/ml) | 22.44 | 0.40 |
Solubility factor | 334.44 | 50.0 |
Permeability (cm/s × 10−4) | 2.7 | 2.7 |
Fraction unbound in plasma (%) | 4.57 | 4.57 |
Blood plasma ratio | 0.71 | 0.71 |
Liver clearance (l/h) | 40.0 | 4.0 |
FaSSIF (mg/ml) | 0.003 | 0.003 |
FeSSIF (mg/ml) | 0.117 | 0.7 |
Solubilization ratio | 1.03E+04 | 8.01E+04 |
Particle radius/diameter (µm) | 25/50 | 15/30 |
Mean precipitation time (s) | 900 | 100 |
Input data for the model
Modeling strategy
Results
Patients characteristics
Characteristics | Week 1 | Week 2–50 |
---|---|---|
(n = 26) | (n = 10) | |
Gender n (%) | ||
Female | 14 (53.8%) | 6 (60%) |
Male | 12 (46.2%) | 4 (40%) |
Age (years) | ||
Median (min–max) | 65.5 (47–80) | 65.5 (55–74) |
Body weight (kg) | ||
Median (min–max) | 68.5 (44–97) | 63.0 (44–84) |
Body height (cm) | ||
Median (min–max) | 170.0 (156.0–186.0) | 170.0 (156.0–186.0) |
Body surface (m2) | ||
Median (min–max) | 1.79 (1.36–2.22) | 1.69 (1.36–2.06) |
Long time performance
Time | Parameters | Dimension | Observed | Simulated | ||||
---|---|---|---|---|---|---|---|---|
Meana±SD | Min–max |
N
| Meana | Min–max |
N
| |||
Day 1 |
C
peak
| µg/ml | 0.84 ± 0.54 | 0.21–1.82 | 26 | 0.78 | 0.60–0.99 | 25 |
C
last
| µg/ml | 0.33 ± 0.29 | 0.04–1.22 | 26 | 0.30 | 0.29–0.31 | 25 | |
T
max
| h | 2.00 | 1.00–8.00 | 26 | 1.89 | 1.20–2.90 | 25 | |
AUC0–24 | µg-h/ml | 12.47 ± 9.38 | 1.23–36.37 | 26 | 11.47 | 9.57–14.07 | 25 | |
T
1/2el
| h | 18.72 ± 13.10 | 4.10–59.00 | 26 | 10.90 | nc | 25 | |
V
d
| l | 97.86 ± 61.72 | 18.00–268.09 | 26 | 67.80 | nc | 25 | |
Cltot | l/h | 5.51 ± 5.73 | 0.47–30.09 | 26 | 4.30 | nc | 25 | |
Day 3 |
C
trough
| µg/ml | 0.45 ± 0.37 | 0.003–1.51 | 26 | 0.44 | 0.40–0.48 | 25 |
C
peak
| µg/ml | 1.04 ± 0.62 | 0.19–2.99 | 26 | 1.04 | 0.98–1.10 | 25 | |
Day 6 |
C
trough
| µg/ml | 0.72 ± 0.53 | 0.05–2.20 | 26 | 0.51 | 0.46–0.56 | 25 |
C
peak
| µg/ml | 1.38 ± 0.66 | 0.11–3.24 | 26 | 1.09 | 1.02–1.15 | 25 |
Patients | Weeks |
N
|
C
trough
a
| Min–max |
---|---|---|---|---|
Pat.1 | 1–15 | 10 | 1.67 ± 0.44 | 0.77–2.20 |
Pat.2b | 1–9 | 9 | 0.16 ± 0.04 | 0.12–0.23 |
Pat.3 | 1–50 | 50 | 0.89 ± 0.68 | 0.09–2.68 |
Pat.4 | 1–8 | 7 | 0.66 ± 0.27 | 0.14–1.06 |
Pat.5b | 1–4 | 4 | 0.37 ± 0.09 | 0.25–0.46 |
Pat.6 | 1–8 | 8 | 1.78 ± 0.74 | 0.73–3.06 |
Pat.7 | 1–9 | 9 | 1.20 ± 0.51 | 0.31–1.80 |
Pat.8b | 1–16 | 16 | 0.27 ± 0.38 | 0.02–1.31 |
Pat.9b | 1–50 | 47 | 0.06 ± 0.04 | 0.01–0.16 |
Pat.10b | 1–11 | 11 | 0.16 ± 0.06 | 0.07–0.31 |