Table 4.
Results of the pharmacokinetic–pharmacodynamic final models
| Parameter | Model results, mean (RSE %) | Bootstrap median (95% CI) |
|---|---|---|
| Absolute neutrophil count | ||
| BASE, 109/L | 3.7 (14.9) | 3.6 (2.8–4.8) |
| MTT, h | 207 (12.2) | 209 (163–249) |
| Emax | 0.16 (15.1) | 0.16 (0.11–0.21) |
| EC50, ng/mL | 1.8 (149) | 1.7 (0.3–18.4) |
| POW | 0.27 (31.6) | 0.28 (0.16–0.41) |
| GAM | Fixed to 1 (NA) | Fixed to 1 (NA) |
| ω(BASE), % | 50.8 (37.6) | 48.8 (32.4–67.4) |
| ω(EC50), % | 133 (294) | 124 (1.3–237) |
| σ, % | 38.8 (6.7) | 38.1 (32.7–42.8) |
| Alanine transaminase | ||
| BASE, UL | 26.5 (6.6) | 26.5 (23.3–30.8) |
| kout, 1/h | 0.00559 (31.1) | 0.00553 (0.00131–0.00195) |
| kPD, mL/ng | 0.00443 (28.9) | 0.00469 (0.00131–0.00873) |
| ω(BASE), % | 44.7 (24.7) | 44.0 (35.2–54.4) |
| ω(kout), % | 70.7 (118) | 62.7 (1.1–114) |
| ω(kPD), % | 97.9 (56.4) | 99.7 (63.5–186) |
| σ, % | 33.9 (2.2) | 33.6 (26.2–42.2) |
| Aspartate transaminase | ||
| BASE, UL | 26.2 (8.3) | 26.1 (23.1–29.4) |
| kout, 1/h | 1.7 (703) | 1.5 (0.03–9.5) |
| kPD, mL/ng | 0.00492 (32.7) | 0.00487 (0.00341–0.0064) |
| ω(BASE), % | 29.5 (30.0) | 28.7 (17.8–38.0) |
| ω(kout), % | 435 (529) | 369 (4.5–648) |
| ω(kPD), % | 2.1 (420) | 1.5 (0.04–23.8) |
| σ, % | 31.2 (2.7) | 31.0 (21.7–40.4) |
| Diastolic blood pressure | ||
| BASE, mmHg | 65.9 (3.1) | 65.5 (62.4–68.7) |
| kout, 1/h | 0.0170 (122) | 0.0176 (0.0341–62.8) |
| kPD, mL/ng | 0.00225 (47.6) | 0.00255 (0.00138–0.0056) |
| ω(BASE), % | 9.6 (56.7) | 9.4 (6.7–11.6) |
| ω(kout), % | 117 (672) | 120 (1.2–515) |
| ω(kPD), % | 50.5 (227) | 35.7 (0.5–103) |
| σ, % | 9.4 (7.7) | 9.2 (7.2–11.0) |
| Hemoglobin | ||
| BASE, 109/L | 13.0 (1.8) | 13.0 (12.6–13.4) |
| MTT, h | 1,370 (13.0) | 1,379 (800–3,080) |
| kPD, mL/ng | 0.000317 (59.0) | 0.000580 (0.0000471–0.00355) |
| POW | Fixed to 1 (NA) | Fixed to 1 (NA) |
| ω(BASE), % | 12.1 (16.8) | 12.0 (9.2–15.0) |
| ω(kPD), % | 262 (35.8) | 198 (59.4–490) |
| σ, % | 5.8 (2.7) | 5.7 (5.1–6.4) |
| Lymphocyte count | ||
| BASE, 109/L | 1.5 (11.8) | 1.5 (1.2–1.8) |
| MTT, h | 1,990 (15.5) | 1,997 (1239–3,111) |
| Emax | 1 (Fixed) | 1 (Fixed) |
| EC50, ng/mL | 165 (181) | 153 (1.7–6.28) |
| POW, | Fixed to 1 (NA) | Fixed to 1 (NA) |
| GAM | Fixed to 1 (NA) | Fixed to 1 (NA) |
| ω(BASE), % | 49.3 (54.3) | 48.1 (38.4–57.6) |
| ω(EC50), % | 404 (109) | 453 (4.0–1.36) |
| σ, % | 24.3 (5.8) | 24.1 (20.9–27.1) |
| Platelet count | ||
| BASE, 109/L | 242 (5.4) | 243 (221–267) |
| MTT, h | 173 (8.6) | 172 (129–201) |
| Emax | 0.14 (7.1) | 0.17 (0.08–0.37) |
| EC50, ng/mL | 64.9 (33.3) | 94.6 (34.4–269) |
| POW | 0.19 (13.6) | 0.19 (0.09–0.28) |
| GAM | Fixed to 1 (NA) | Fixed to 1 (NA) |
| ω(BASE), % | 34.2 (20.7) | 33.6 (27.0–41.0) |
| ω(EC50), % | 167 (33.2) | 122 (68.5–232) |
| σ, % | 16.7 (2.9) | 16.3 (14.4–18.7) |
| White blood cell count | ||
| BASE, 109/L | 6.1 (6.0) | 6.1 (5.3–6.9) |
| MTT, h | 230 (6.3) | 229 (167–272) |
| Emax | 0.1 (10.2) | 0.1 (0.06–0.19) |
| EC50, ng/mL | 7.1 (77.5) | 7.1 (0.2–69.1) |
| POW | 0.28 (16.9) | 0.28 (0.13–0.43) |
| GAM | Fixed to 1 (NA) | Fixed to 1 (NA) |
| ω(BASE), % | 42.8 (20.8) | 42.5 (33.2–51.7) |
| ω(EC50), % | 240 (62.6) | 242 (45.2–558) |
| σ, % | 26.0 (2.9) | 25.7 (22.3–29.4) |
BASE baseline endpoint value, CI confidence interval, EC50 concentration at half maximum effect, GAM Hill coefficient in the sigmoid, Emax effect model, kout output/elimination rate constant, kPD effect first-order rate constant, MTT mean transit time, NA not available, POW exponent on the feedback loop function, RSE relative standard error, σ residual variability, ω interindividual variability