Table 3.
Axitinib pharmacokinetic parameter estimates for base and final models
| Parameter | Base | Final | ||||
|---|---|---|---|---|---|---|
| Estimate | %RSE* | 95% CI† | Estimate | %RSE* | 95% CI† | |
| Structural model parameters | ||||||
| CL (l h−1) | 17.1 | 8.2 | 14.6, 20.1 | 17.0 | 6.6 (8.2) | 14.9, 19.4 |
| Vc (l) | 46.6 | 7.6 | 40.2, 54.0 | 45.3 | 6.4 (8.3) | 40.0, 51.3 |
| Weight effect on Vc | – | – | – | 0.758 | 14 (14) | 0.556, 0.960 |
| Q (l h−1) | 1.73 | 8.2 | 1.47, 2.03 | 1.74 | 9.2 (16) | 1.45, 2.08 |
| Vp (l) | 44.7 | 20 | 30.5, 65.6 | 45.9 | 25 (57) | 28.0, 75.3 |
| ka (h−1) Form IV, Fed | 0.530 | 6.8 | 0.464, 0.605 | 0.523 | 7.6 (7.0) | 0.450, 0.607 |
| Fasting | 2.10 | 13 | 1.55, 2.65 | 2.07 | 14 (14) | 1.49, 2.65 |
| F, Form IV, Fed | 0.469 | 7.8 | 0.403, 0.546 | 0.465 | 7.2 (8.4) | 0.403, 0.536 |
| Fasting | 0.323 | 15 | 0.228, 0.418 | 0.338 | 15 (14) | 0.240, 0.436 |
| Form XLI | −0.147 | 24 | −0.216, −0.0780 | −0.150 | 23 (23) | −0.219, −0.0814 |
| tlag (h)‡ | 0.457 | 0.32 | 0.454, 0.460 | 0.457 | – | – |
| Interindividual variability model parameters§ | ||||||
| ω2 CL | 0.270 | 11 | 0.216, 0.337 | 0.272 | 14 (11) | 0.208, 0.355 |
| ω2Vc | 0.140 | 15 | 0.104, 0.188 | 0.0949 | 25 (18) | 0.0579, 0.155 |
| ω2 Q | 0.380 | 23 | 0.244, 0.591 | 0.406 | 22 (27) | 0.266, 0.619 |
| ω2Vp | 1.06 | 34 | 0.549, 2.05 | 1.07 | 33 (44) | 0.566, 2.02 |
| ω2 ka | 0.476 | 14 | 0.360, 0.629 | 0.506 | 13 (13) | 0.392, 0.654 |
| ω CL ω Vc | 0.158 | 14 | 0.114, 0.202 | 0.141 | 22 (15) | 0.0812, 0.201 |
| ω Q ω Vp | 0.593 | 28 | 0.272, 0.914 | 0.619 | 26 (35) | 0.300, 0.938 |
| Residual error model parameters | ||||||
| Oral, % | 50.9 | 2.7 | 48.3, 53.7 | 50.9 | 2.7 (2.9) | 48.3, 53.7 |
| Intravenous, % | 34.2 | 15 | 25.5, 45.9 | 34.8 | 16 (14) | 25.4, 47.7 |
%RSE of model parameter estimates obtained from the nonmem covariance step. %RSE shown in parenthesis for the final model were obtained from non-parametric bootstrap of 200 samples (91% successful minimization).
Confidence interval was calculated as estimate × exp (± 1.96 %RSE/100), or for quantities that could be positive or negative (covariate parameters and covariances), it was calculated as estimate ± 1.96 %RSE/100 to allow the interval to span 0.
The final model was run again with tlag fixed to 0.457 in bullet to obtain a successful covariance step and calculate %RSE. Estimates with fixed tlag matched the final run or differed by no more than 2 in the last significant digit.
Interindividual variability was calculated as √ω2 × 100. CI, confidence interval; CL, systemic clearance; F, absolute bioavailability; ka, first-bullet rate of absorption; Q, peripheral clearance; RSE, relative standard error; tlag, absorption lag time; Vc, central volume of distribution; Vp, peripheral volume of distribution.