Table 5.
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 70 kg−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 | 17 (0%, 13.5–21.3) | 79.7 | 80.3 (0.8%, 64.8, 97.3) |
| θ2 | 0.462 | 0.463 (0.2%, 0.060, 0.954) | 0.679 | 0.682 (0.4%, 0.284, 1.070) |
| CLR (l h−1) | 11.1 | 11.2 (0.9%, 6.8, 14.6) | 50.7 | 49.8 (−1.8%, 34.8, 66.1) |
| V1 (l) | 13.2 | 13.3 (0.8%, 11.0, 15.6) | 63.8 | 65.0 (1.9%, 50.6, 78.1) |
| Q (l h−1) | 30.6 | 30.5 (−0.3%, 26.5, 34.2) | 152 | 146.5 (−3.6%, 123.0, 171.0) |
| V2 (l) | 15 | 15 (0%, 13.8, 16.2) | 71.6 | 70.3 (−1.8%, 62.7, 78.4) |
| Interindividual variability | ||||
| ωCL (CV%) | 26.7 | 26.7 (0%, 21.7, 31.8) | 29.8 | 29.8 (0%, 23.0, 37.1) |
| ωV1 (CV%) | 57.9 | 57.9 (0%, 38.0, 75.9) | 38.7 | 39.8 (2.8%, 17.6, 65.6) |
| ωQ (CV%) | 41.1 | 41.5 (1%, 27.3, 55.9) | 49.6 | 46.3 (−6.7%, 26.9, 60.5) |
| ωV2 (CV%) | 34.5 | 34.1 (−1.2%, 25.9, 42.9) | 35.4 | 37.6 (6.2%, 26.8, 49.2) |
| Random residual variability | ||||
| σ1 (SD) | 0.072 | 0.072 (0%, 0.060, 0.083) | 0.138 | 0.131 (−5.1%, 0.104, 0.155) |
| σ2 (SD) | 0.082 | 0.081 (−1.2%, 0.060, 0.107) | 0.027 | 0.028 (3.7%, 0.003, 0.051) |
| OBV | −876 | −1535 | ||
| Structural models: | ||||
| CL = CLNR+ CLR, where CLNR=θ1× (HCT/34)θ2× (FFM/50)0.75 and CLR=θ3× (CLcr/88), 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 70 kg−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.