Table 2.
Population PK covariate analysis of tremelimumab from the DETERMINE trial
| Hierarchical model | Covariate‐PK relationship | Covariate‐PK relationship strength | OFV likelihood | Reference OFV | P value |
|---|---|---|---|---|---|
| 1. Base model | None | – | 10,428 | – | – |
| 2. Intermediate model 1 | CL % reduction for female patients vs. male | −0.19 |
10,414 (Δ = −14) |
1 | 0.00018 |
| 3. Intermediate model 2 | Serum albumin on CL | 0.00094 |
10,413 (Δ = −1) |
2 | 0.32 |
| 4. Intermediate model 3 | CRP effect on CL | 0.0034 |
10,370 (Δ = −44) |
2 | < 10−10 |
| 5. Intermediate model 4 | ECOG effect on CL | 0.019 |
10,368 (Δ = −1.4) |
4 | 0.24 |
| 6. Intermediate model 5 | EORTC effect on CL | 0.068 |
10,368 (Δ = −2.0) |
4 | 0.16 |
| 8. Intermediate model 6 | LDH effect on CL | −2.1 × 10−04 |
10,364 (Δ = −1.3) |
7 | 0.26 |
| 5. Intermediate model 7 | Histology (epithelioid) % increase on CL | 0.084 |
10,363 (Δ = −1.7) |
7 | 0.19 |
| 7. Final model | Baseline tumor size effect on CL | 0.00058 |
10,365 (Δ = −4.3) |
4 | 0.039 |
Continuous covariates were entered in the model assuming proportional linear effect of the covariate on PK from median cutoff (median is 31 g/L for albumin, 33 mg/L for CRP, and 97 mm for baseline tumor size). Sex, CRP, and baseline tumor size were significant PK predictors and explained 20% of the interindividual variability on CL, reducing coefficient of variation from 42% to 38%. ΔOFV was computed for nested models according to the order displayed in the “Reference OFV” column, where the reference OFV is taken as the previous model with the statistically significant covariate‐PK relationship included.
CL, clearance; CRP, C‐reactive protein; ECOG, Eastern Cooperative Oncology Group; EORTC, European Organisation for Research and Treatment of Cancer; LDH, lactate dehydrogenase; OFV, objective function value; PK, pharmacokinetic.