A mathematical/statistical model to describe the disposition of olaratumab was developed using data from four clinical studies. |
The model describes the time course of olaratumab disposition in the body of all patients included in the analysis and predicts disposition in additional patient populations. |
The described model is the most comprehensive understanding of the pharmacokinetic properties of olaratumab. |
1 Introduction
2 Materials and Methods
2.1 Study Design and Study Population
2.2 Model Development and Analysis
Covariate | Type | Parameters tested |
---|---|---|
Age | Continuous | CL, V
1, V
2, Q
|
Body weight | Continuous | CL, V
1, V
2, Q
|
Body mass index | Continuous | CL, V
1, V
2, Q
|
Body surface area | Continuous | CL, V
1, V
2, Q
|
Sex | Categorical | CL, V
1, V
2, Q
|
Race | Categorical | CL, V
1, V
2, Q
|
Ethnicity | Categorical | CL, V
1, V
2, Q
|
Calculated creatinine clearance | Continuous | CL, V
1, V
2, Q
|
Albumin | Continuous | CL, V
1, V
2, Q
|
Aspartate transaminase | Continuous | CL, V
1, V
2, Q
|
Alanine transaminase | Continuous | CL, V
1, V
2, Q
|
Alkaline phosphatase | Continuous | CL, V
1, V
2, Q
|
Total bilirubin | Continuous | CL, V
1, V
2, Q
|
Absolute dose (mg) | Continuous | CL, V
1, V
2, Q
|
Treatment dose (mg/kg) | Categorical | CL, V
1, V
2, Q
|
Cancer indication | Categorical | CL, V
1, V
2, Q
|
Tumor size (mm) | Continuous | CL, V
1, V
2, Q
|
Chemotherapeutic agent | Categorical | CL, V
1, V
2, Q
|
3 Results
3.1 Data Summary
Patient demographics |
N (%) | Study designs |
N (%) |
---|---|---|---|
Gender | Treatment combination | ||
Female | 87 (51) | ||
Male | 84 (49) | Paclitaxel/carboplatin | 45 (26) |
Race | Doxorubicin | 73 (43) | |
Caucasian | 147 (86) | Monotherapy | 53 (31) |
African descent | 15 (8.8) | Treatment regimen | |
Asian (east/southeast) | 2 (1.2) | ||
Asian (western) | 1 (0.6) | Days 1 and 8 of a 21-day cycle | 145 (85) |
Native Hawaiian Other Pacific Islander | 1 (0.6) | Day 1 of a 14-day cycle | 26 (15) |
Other | 5 (2.9) |
Patient characteristics | |||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Age (years) | Height (cm) | Weight (kg) | BSA (m2) | BMI (kg/m2) | LBM (kg) | TUMR (mm) | CGCL (mL/min) | ALB (g/L) | ALP (U/L) | ALT (U/L) | AST (U/L) | TBI (µmol/L) | |
All four studies | |||||||||||||
N
| 171 | 170 | 171 | 170 | 170 | 170 | 164 | 143 | 143 | 143 | 144 | 144 | 143 |
Mean | 56.8 | 170 | 80.6 | 1.90 | 27.6 | 52.5 | 107 | 109 | 37.7 | 99.4 | 26.2 | 22.9 | 7.95 |
SD | 11.7 | 9.48 | 21.8 | 0.259 | 6.69 | 9.78 | 85.4 | 45.5 | 4.68 | 56.0 | 16.0 | 12.4 | 3.8 |
Median | 57.0 | 168 | 79.7 | 1.88 | 26.5 | 52.5 | 86.5 | 99.7 | 38.0 | 86.0 | 21.0 | 20.0 | 6.84 |
Min | 22.0 | 151 | 37.3 | 1.33 | 16.1 | 33.6 | 12.0 | 40.2 | 22.0 | 4.80 | 4.00 | 5.00 | 1.71 |
Max | 82.0 | 197 | 151 | 2.59 | 53.6 | 79.8 | 571 | 250 | 49.0 | 463 | 88.0 | 96.0 | 25.6 |
Geo mean | 55.4 | 169 | 77.8 | 1.88 | 26.9 | 51.7 | 80.8 | 100 | 37.4 | 88.8 | 22.1 | 20.4 | 7.13 |
Geo CV% | 23.7 | 5.56 | 26.7 | 13.7 | 22.7 | 18.8 | 91.8 | 41.2 | 13.4 | 51.2 | 63.6 | 50.3 | 50.6 |
3.2 Base Model Development
Parameter descriptions | Base PK model | Final PK model | ||||
---|---|---|---|---|---|---|
Population estimates (%SEE) | Interpatient variability (%SEE) | Population estimates (%SEE) | Interpatient variability (%SEE) | Bootstrap results (95% CI) | Bootstrap results of interpatient variability (95% CI) | |
Structural model | ||||||
Clearance, CL (L/h) | 0.0241 (4.02) | 38.2% (15.7) | 0.0233 (3.67) | 33.3% (12.9) | 0.0233 (0.0215–0.0253) | 32.8% (27.7–38.0) |
Central volume of distribution, V
1 (L) | 4.19 (4.32) | 22.2% (18.8) | 4.16 (1.79) | 15.6% (30.1) | 4.15 (3.99–4.31) | 15.4% (11.4–19.1) |
Peripheral volume of distribution, V
2 (L) | 3.58 (20.1) | – | 3.58 (13.2) | – | 3.66 (2.69–4.90) | |
Intercompartmental clearance, Q (L/h) | 0.0316 (25.6) | – | 0.0315 (25.8) | – | 0.0335 (0.0196–0.0524) | |
Residual error model | ||||||
Additive (µg/mL) | 9.78 (56.2) | 10.1 (15.5) | 11.4 (3.56–31.5) | |||
Proportional | 22.6% (24.8) | 22.5% (18.1) | 22.2 (16.5–27.2) | |||
Covariate model | ||||||
WTECL
a
| – | 0.431 (10.2) | 0.433 (0.216–0.654) | |||
\( {\text{WTE}}_{{V_{ 1} }} \)
b
| – | 0.610 (12.9) | 0.611 (0.476–0.760) | |||
TUMRCL
a
| – | 0.00158 (25.8) | 0.00159 (0.000817–0.00252) |