Table 3.
Parameter and Covariate Parameter Estimates for the Population PK Model
| Parameter Estimates and Bootstrap Results | ||||||
|---|---|---|---|---|---|---|
| Final Model | Bootstrap a | |||||
| Estimates (RSE%) | IIV (RSE%) | IOV (RSE%) | Median (IIV%) | 95%CI | 95%CI for IIV | |
| CL/F, L/h | 26.3 (1.2) | 22.2 (7.7) | NA | 26.3 (22.2) | 25.5‐27.2 | 19.0‐24.5 |
| V/F, L | 115.8 (1.1) | NA | NA | 115.5 (NA) | 111.5‐120.6 | NA |
| Ka, h−1 | 9.9 (7.1) | NA | 191.8 (7.0) | 9.86 (191.9) b | 7.9‐10.8 | 179.0‐205.0 b |
| Proportional error, TAD ≤8 h, % | 41.6 (2.6) | 58.0 (6.3) | NA | 41.3 (58.0) | 38.6‐44.4 | 54.0‐62.2 |
| Proportional error, TAD >8 h, % | 68.9 (2.6) | 58.0 (6.3) | NA | 68.6 (58.0) | 64.1‐73.5 | 54.0‐62.2 |
| Lag time, h | 0.236 (0.52) | NA | NA | 0.236 (NA) | 0.218‐0.238 | NA |
| Scaling parameter c | 0.392 (7.19) | NA | NA | 0.399 (NA) | 0.305‐0.481 | NA |
| Covariate Parameter Estimates | ||||||
| PK Parameter | Covariate | Estimate d | RSE% | 95%CI e | ||
| CL/F | BCCL | 0.354 | 7.57 | 0.279‐0.426 | ||
| CL/F | Female | 0.868 | 1.86 | 0.829‐0.909 | ||
| CL/F | Asian | 0.932 | 2.16 | 0.888‐0.972 | ||
| V/F | Age | –0.116 | 15.05 | −0.173 to −0.065 | ||
| V/F | Female | 0.845 | 1.54 | 0.802‐0.887 | ||
| V/F | Body weight | 0.585 | 5.03 | 0.501‐0.674 | ||
Abbreviations: BCCL, baseline creatinine clearance; CI, confidence interval; CL/F, apparent oral clearance; h, hours; IIV, interindividual variability; IOV, interoccasion variability; Ka, absorption rate constant; NA, not available; PK, pharmacokinetics; RSE, relative standard error; TAD, time after dose; V/F, apparent volume of distribution.
The derived elimination half‐life was approximately 3.05 h.
621 in 1000 runs minimized successfully.
As IOV (%) and 95%CI for IOV, instead of IIV.
A scaling parameter was applied to describe IIV of V/F relative to IIV of CL/F, due to the lack of samples to describe peak and trough concentrations for phase 3 studies and a high estimated correlation between V/F and CL/F.
For continuous covariates, estimates were computed as power functions, normalized to the reference (approximate median) values in the data set; for categorical covariates, estimates were computed as a fraction of the reference category, with 1 estimated coefficient for each category.
95%CI for covariate parameter estimates were calculated based on the bootstrap method.