Table 3.
Population pharmacodynamic parameter estimates
| Parameter | Estimates | RSE % | 95% CI |
|---|---|---|---|
| (a) Coagulation factor X | |||
| GCC4401C from the SAD and S&MAD studies: Sigmoid Emax model | |||
| Emax, % | 81.2 | 11.3 | 63.2–99.2 |
| IIVEmax (CV, %) | 0.10 (33.1) | 48.5 | 0.01–0.20 |
| EC50, ng/mL | 2880.0 | 34.1 | 957.2–4802.8 |
| IIVEC50 (%) | 0.98 (129.4) | 39.0 | 0.23–1.74 |
| γSAD | 1.07 | 14.3 | 0.77–1.37 |
| γSAD/MAD | 0.60 | 11.7 | 0.46–0.74 |
| IIVγ (CV, %) | 0.24 (51.8) | 32.7 | 0.09–0.39 |
| IOVγ (CV, %) | 0.09 (30.1) | 35.3 | 0.03–0.15 |
| ε (additive), % | 3.94 | 22.5 | 2.20–5.68 |
| ε (proportional)e | 0.06 | 12.9 | 0.04–0.07 |
| Rivaroxaban from the S&MAD study (Sigmoid Emax model) | |||
| Emax, % | 42.9 | 19.0 | 26.9–58.9 |
| EC50, ng/mL | 194.0 | 27.4 | 99.9–288.1 |
| IIVEC50 (CV, %) | 0.33 (62.1) | 117.8 | −0.43–1.08 |
| IOVEC50 (CV, %) | 0.25 (52.9) | 155.5 | −0.51–1.00 |
| γ | 0.90 | 21.3 | 0.53–1.28 |
| ε (proportional)e | 0.06 | 6.9 | 0.05–0.06 |
| (b) Factor X chromogenic activity assay | |||
| GCC4401C from the S&MAD study (Sigmoid Emax model) | |||
| Emax, % | 99.8 | 7.3 | 85.5–114.1 |
| IIVEmax (CV, %) | 0.01 (11.3) | 52.1 | 0–0.03 |
| EC50, ng/mL | 420.0 | 16.4 | 284.8–555.2 |
| IIV + IOVEC50 (%) | 0.08 (129.4) | 42.1 | 0.01–0.15 |
| γ | 0.90 | 7.5 | 0.76–1.03 |
| IIVγ (CV, %) | 0.06 (25.7) | 44.9 | 0.01–0.12 |
| ε (additive), % | 3.03 | 34.7 | 0.97–5.1 |
| ε (proportional)e | 0.06 | 18.3 | 0.04–0.08 |
| Rivaroxaban from the S&MAD study (Simple Emax model) | |||
| Emax, % | 112.0 | 3.2 | 104.9–119.1 |
| EC50, ng/mL | 126.0 | 13.1 | 93.7–158.3 |
| IIVEC50 (CV, %) | 0.07 (26.9) | 62.9 | −0.02–0.16 |
| IOVEC50 (CV, %) | 0.01 (8.2) | 90.1 | −0.01–0.02 |
| ε (additive), % | 3.89 | 15.0 | 2.75–5.03 |
| ε (proportional)e | 0.05 | 33.2 | 0.02–0.08 |
| (c) Antifactor Xa activity | |||
| GCC4401C from the S&MAD study (Sigmoid Emax model) | |||
| Emax, IU/mL | 3.24 | 21.3 | 1.89–4.59 |
| IIVEmax (CV, %) | 0.04 (20.8) | 62.3 | 0.00–0.03 |
| EC50, ng/mL | 695.0 | 26.0 | 340.2–1,049.8 |
| IIV + IOVEC50 (%) | 0.005 (7.2) | 48.8 | 0.000–0.01 |
| γ | 1.25 | 6.0 | 1.10–1.40 |
| IIVγ (CV, %) | 0.02 (13.4) | 51.4 | 0.00–0.04 |
| ε (additive), IU/mL | 0.04 | 12.2 | 0.03–0.05 |
| ε (proportional)e | 0.14 | 8.1 | 0.12–0.16 |
| Rivaroxaban from the S&MAD study (Linear model) | |||
| SLOPE | 0.005 | 6.4 | 0.004–0.006 |
| IIVSLOPE (CV, %) | 0.01 (10.8) | 43.7 | 0.00–0.02 |
| ε (additive), IU/mL | 0.04 | 11.7 | 0.03–0.05 |
| ε (proportional)e | 0.29 | 13.0 | 0.21–0.36 |
| (d) PT (INR) | |||
| GCC4401C from the SAD and S&MAD studies (Sigmoid Emax model) | |||
| EMAX, INR | 1.32 | 20.3 | 0.79–1.85 |
| IIVEmax (CV, %) | 0.48 (78.0) | 43.0 | 0.08–0.87 |
| EC50, SAD, ng/mL | 426.0 | 24.4 | 222.2–629.8 |
| EC50, SAD/MAD, ng/mL | 1350.0 | 27.3 | 628.7–2,071.3 |
| IIVEC50 (CV, %) | 0.89 (120.1) | 52.3 | −0.02–1.81 |
| γ | 1.23 | 7.5 | 1.05–1.41 |
| IIVγ (CV, %) | 0.11 (34.3) | 74.1 | −0.05–0.27 |
| IOVγ (CV, %) | 0.04 (19.9) | 69.6 | −0.01–0.09 |
| ε (proportional)e | 0.05 | 7.7 | 0.04–0.06 |
| Rivaroxaban from the S&MAD study (Simple Emax model) | |||
| Emax, INR | 0.71 | 26.5 | 104.9–119.1 |
| EC50, ng/mL | 434.0 | 37.3 | 116.5–751.5 |
| IIV + IOVEC50 (CV, %) | 0.06 (25.8) | 53.9 | 0.00–0.13 |
| ε (additive), INR | 0.04 | 6.2 | 0.04–0.05 |
| (e) Prothrombin time (seconds) | |||
| GCC4401C from the S&MAD study (Sigmoid Emax model) | |||
| Emax, sec | 15.2 | 21.5 | 8.8–21.6 |
| IIVEmax (CV, %) | 0.41 (71.6) | 64.7 | −0.11–0.94 |
| EC50, SAD, ng/mL | 563.0 | 34.3 | 184.7–941.3 |
| EC50, SAD/MAD, ng/mL | 1450.0 | 30.0 | 597.4–2302.6 |
| IIVEC50 (CV, %) | 0.77 (107.8) | 64.5 | −0.20–1.75 |
| γ | 1.16 | 8.0 | 0.98–1.34 |
| IIVγ (CV, %) | 0.04 (18.9) | 65.0 | −0.01–0.08 |
| IOVγ (CV, %) | 0.03 (17.8) | 60.1 | −0.01–0.07 |
| ε (proportional)e | 0.04 | 6.9 | 0.04–0.05 |
| Rivaroxaban from the S&MAD study (Simple Emax model) | |||
| Emax, sec | 6.86 | 39.1 | 1.61–12.11 |
| EC50, ng/mL | 418.0 | 60.3 | −75.9–911.9 |
| IIV + IOVEC50 (CV, %) | 0.07 (26.6) | 71.5 | 0.00–0.13 |
| ε (additive), sec | 0.04 | 9.3 | 0.03–0.04 |
| (f) Activated PT (seconds) | |||
| GCC4401C from the SAD and SAD/MAD studies (Sigmoid Emax model) | |||
| Emax, SAD, sec | 16.9 | 13.1 | 12.5–21.3 |
| Emax, SAD/MAD, sec | 20.4 | 12.5 | 15.4–25.4 |
| IIVEmax (CV, %) | 0.09 (30.3) | 86.1 | −0.06–0.24 |
| EC50, ng/mL | 573.0 | 22.7 | 318.2–827.8 |
| IIVEC50 (CV, %) | 0.33 (62.4) | 62.3 | −0.07–0.73 |
| γ | 1.37 | 13.2 | 1.02–1.72 |
| IIVγ (CV, %) | 0.19 (45.9) | 39.2 | 0.04–0.34 |
| IOVγ (CV, %) | 0.03 (17.8) | 35.5 | 0.02–0.11 |
| ε (proportional)e | 0.05 | 1.0 | 0.05–0.05 |
| Rivaroxaban from the S&MAD (Sigmoid Emax model) | |||
| Emax, sec | 12.4 | 10.3 | 9.9–14.9 |
| EC50, ng/mL | 135.0 | 14.3 | 97.2–172.8 |
| γ | 0.94 | 18.1 | 0.61–1.28 |
| IIV + IOVγ (CV, %) | 0.27 (55.7) | 38.5 | 0.07–0.47 |
| ε (additive), sec | 0.04 | 9.3 | 0.03–0.04 |
| (g) AT III activity | |||
| GCC4401C from the SAD study (Linear model) | |||
| SLOPE | 0.006 | 44.8 | 0.001–0.011 |
| IIVSLOPE (CV, %) | 3.73 (637.8) | 38.6 | 0.91–6.55 |
| ε (additive) | 9.28 | 10.9 | 7.30–11.3 |
| (h) LMWH | |||
| GCC4401C from the SAD study (Simple Emax model) | |||
| Emax | 3.83 | 11.4 | 2.98–4.68 |
| IIVSLOPE (CV, %) | 3.73 (637.8) | 38.6 | 0.91–6.55 |
| EC50, ng/mL | 759.0 | 15.2 | 533.6–984.4 |
| IIVEC50 (CV, %) | 0.29 (57.4) | 33.9 | 0.10–0.47 |
| ε (additive) | 0.08 | 20.6 | 0.05–0.11 |
| ε (proportional)e | 0.17 | 14.3 | 0.12–0.22 |
AT III, antithrombin III; CI, confidence interval; CV, %, % coefficient of variation (CV), calculated by CV (%)=sqrt(exp(omega)−1))*100; EC50, plasma GCC4401C concentration at half‐maximum effect; Emax, maximum achievable effect in the maximum effect model; IIV, interindividual variability; INR, international normalized ratio; IOV, interoccasional variability, variance (% coefficient of variation (CV), calculated by CV (%)=sqrt(exp(omega)−1))*100; LMWH, low‐molecular‐weight heparin; PT, prothrombin time; RSE, relative standard error (standard error divided by the parameter estimate); S&MAD, single and multiple‐ascending dose; SAD, single ascending dose trial; SAD/MAD, single and multiple ascending dose trial; γ, shape parameter in sigmoid maximum effect model.e ε (proportional) is represented as SDs.