Table I.
Parameter Estimates of Final PK/PD Model
| Phase IIa studies dataset | Combined dataset | |||||
|---|---|---|---|---|---|---|
| NONMEM | Bootstrap analysesc | NONMEM | ||||
| Parameter | Value | RSE,% | Value | 5th–95th percentile | Value | RSE,% |
| Fixed Effects PK | ||||||
| ka [1/h] | 0.69 | FIX | 0.69 | FIX | 0.602 | 15.7 |
| V2/F [L] | 720 | 4.9 | 716 | 665–779 | 694 | 2.3 |
| CLnon-met/F [L/h] | 1.31 | 5.5 | 1.31 | 1.19–1.43 | 1.16 | 3.0 |
| CLmet/F [L/h] | 0.416 | 6.9 | 0.413 | 0.373–0.457 | 0.430 | 3.8 |
| V3/F [L]d | 553 | FIX | 550 | FIX | 533 | FIX |
| CLM1/F [L/h] | 1.17 | 8.2 | 1.15 | 1.03–1.31 | 1.01 | 3.9 |
| Fixed Effects PD | ||||||
| keo [1/h] | 0.0001 | FIX | 0.0001 | FIX | 0.0001 | FIX |
| EMAX | −1.46 | 29.3 | −1.57 | −2.57–−0.93 | −2.25 | 13.2 |
| EC50 [ng/mL] | 0.0139 | 49.6 | 0.0139 | 0.0064–0.123 | 0.407 | 26.3 |
| Fixed Effects Placebo | ||||||
| keq [1/h] | 0.00183 | FIX | 0.00183 | FIX | 0.00183 | FIX |
| kel [1/h] | 0.000473 | FIX | 0.000473 | FIX | 0.000473 | FIX |
| β | −1.42 | FIX | −1.42 | FIX | −1.42 | FIX |
| Random Effects | ||||||
| ωCLnon-met/F [CV%]a | 42.2 | 23.8 | 41.3 | 32.4–49.9 | 68.3 | 15.4 |
| ωCLM1/F [CV%]a | 21.3 | 23.9 | 20.3 | 15.7–24.8 | 26.8 | 11.4 |
| ωV2/F [CV%]a | 30.3 | 24.4 | 30.0 | 24.1–36.0 | 35.6 | 13.2 |
| ωV3/F [CV%]a | 42.5 | 39.3 | 41.2 | 27.4–52.1 | 40.1 | 16.0 |
| ωEMAX [CV%]a | 97.7 | 35.7 | 97.6 | 64.6–131 | 108 | 12.5 |
| ωβ [CV%]a | 128 | FIX | 128 | FIX | 128 | FIX |
| Corr CLnon–met/F_V2/F | 0.72 | 28.9 | 0.717 | 0.653–0.774 | 0.645 | 17.2 |
| prop errtesofensine [%]a | 14.9 | 23.5 | 14.4 | 11.7–17.6 | 24.3 | 9.1 |
| prop errM1 [%]a | 17.3 | 36.9 | 16.9 | 14.0–23.6 | 19.1 | 10.8 |
| add errADAS-Cog | ±2.3 | 19.5 | ±2.2 | 1.9–2.7 | ±4.0 | 11.3 |
RSE Relative standard error
aRSE is given on the variance scale
bRSE of the covariance estimate
cbased on 500 bootstrap runs
d0.768-fold of V2/F