Table 6.
Population pharmacokinetic parameter estimates for total and unbound melphalan in 100 patients with multiple myeloma using separately developed Covariate Models that incorporated CLcr with units ml min−1
| Total melphalan | Unbound melphalan | |||
|---|---|---|---|---|
| Parameter | Mean | Bootstrap mean (%diff, 95% CI) | Mean | Bootstrap mean (%diff, 95% CI) |
| Fixed effects | ||||
| CLNR (l h−1) | ||||
| θ1 | 17.5 | 17.7 (1.1%, 14.1, 22.6) | 81.1 | 81.3 (0.2%, 64.7, 100) |
| θ2 | 0.402 | 0.358 (−10.9%, −0.073, 0.930) | 0.587 | 0.615 (4.8%, 0.216, 1.070) |
| CLR (l h−1) | 10.4 | 10.3 (−1.0%, 5.6, 13.5) | 49.7 | 49.1 (−1.2%, 49.3, 64.6) |
| V1 (l) | 13.2 | 13.2 (0%, 10.9, 15.8) | 69.3 | 68.5 (−1.2%, 50.6, 78.1) |
| Q (l h−1) | 30.2 | 30.3 (0.3%, 26.4, 34.4) | 144 | 142.8 (−0.8%, 118.0. 169.0) |
| V2 (l) | 14.8 | 14.9 (0.7%, 13.7, 16.2) | 69.7 | 69 (−1.0%, 61.2, 76.9) |
| Interindividual variability | ||||
| ωCL (CV%) | 26.8 | 26.8 (0%, 21.9, 31.5) | 27.8 | 28.5 (2.5%, 21.6, 36.6) |
| ωV1 (CV%) | 59.2 | 62.6 (5.7%, 43.4, 79.8) | 26.4 | 39.1 (48.1%, 12.9, 68.0) |
| ωQ (CV%) | 40.2 | 41.1 (2.2%, 26.6, 55.1) | 45.4 | 46.1 (1.5%, 26.6, 61.6) |
| ωV2 (CV%) | 34.5 | 33.7 (−2.6%, 30.6, 42.9) | 41.0 | 37.2 (−9.3%, 25.3, 49.9) |
| Random residual variability | ||||
| σ1 (SD) | 0.071 | 0.071 (0%, 0.060, 0.082) | 0.135 | 0.131 (−3.0%, 0.104, 0.155) |
| σ2 (SD) | 0.082 | 0.080 (−2.4%, 0.059, 0.106) | 0.029 | 0.029 (0%, 0.004, 0.053) |
| OBV | −868 | −1525 | ||
| Structural models: | ||||
| CL = CLNR+ CLR, where CLNR=θ1× (HCT/34)θ2× (FFM/50)0.75 and CLR=θ3× (CLcr/97), V1 =θ4× (FFM/50), Q =θ5, V2 =θ6 | ||||
95% CI = lower and upper limits of the 95% confidence interval for population pharmacokinetic parameters obtained with 1000 bootstrap runs. %diff = (bootstrap mean – Covariate model mean)/Covariate model mean × 100, OBV = objective function value. CL, clearance; CLcr, estimated creatinine clearance (ml min−1); %CV, coefficient of variation; FFM, fat free mass (kg); HCT, haematocrit (%); Q, Intercompartmental clearance; SD, standard deviation; V1, Volume of distribution into the central compartment; V2, Volume of distribution into the peripheral compartment; WT, weight.