Table 3.
Population pharmacokinetic and pharmacodynamic parameter estimates
| Parameter | NONMEM estimates | NONMEM RSE (%) | Bootstrap estimates | Bootstrap RSE (%) | 95% CI | ||
|---|---|---|---|---|---|---|---|
| 5FU | |||||||
| CL5FU (L/h) | 256 | 5.47 | 249 | 6.36 | 224–276 | ||
| VC,5FU (L) | 5.85 | 39.3 | 5.56 | 42.0 | 2.41–9.87 | ||
| VP,5FU (L) | 24.0 | 22.9 | 28.5 | 81.5 | 13.3–59.3 | ||
| Q (L/h) | 17.3 | 30.7 | 14.8 | 29.8 | 9.66–23.4 | ||
| BSA effect (m−2)a | 0.71 | 23.5 | 0.77 | 28.0 | 0.44–1.14 | ||
| AUC24,5FU (mg h/L)b | 6.72 | – | 6.72 | – | 4.76–8.74 | ||
| 5FUH2 | |||||||
| Fm (%) | 85 | – | 85 | – | Fixed | ||
| CL5FUH2 (L/h) | 124 | 6.61 | 121 | 7.11 | 108–136 | ||
| VC,5FUH2 (L) | 100 | 13.0 | 96.7 | 14.37 | 74.8–119 | ||
| AUC24,5FUH2 (mg h/L)b | 12.2 | – | 12.2 | – | 7.12—19.2 | ||
| Total WBC count | |||||||
| CIRC0 (× 109/L) | 7.16 | 5.23 | 6.86 | 4.50 | 6.38–7.37 | ||
| MTT (h) | 261 | 6.70 | 281 | 13.1 | 224–344 | ||
| Slopecomb (L/mg) | 2.10 | 18.9 | 2.82 | 27.2 | 1.53–3.77 | ||
| Slopemono (L/mg) | 1.31 | 44.2 | 1.17 | 25.0 | 0.78–1.72 | ||
| γ | 0.17 | – | 0.17 | – | Fixed | ||
| IIV (%CV) | |||||||
| CL5FU | 24.9 | 17.2 | 23.0 | 43.1 | 12.3–30.1 | ||
| VC,5FU | 130 | 45.4 | 145 | 57.0 | 75.3–204 | ||
| CL5FUH2 | 30.5 | 27.1 | 28.9 | 28.0 | 21.8–35.1 | ||
| VC,5FUH2 | 58.9 | 62.7 | 59.6 | 76.8 | 30.7–96.3 | ||
| CIRC0 | 16.8 | 69.6 | 16.4 | 52.0 | 8.29–22.8 | ||
| RUV (σ2) | |||||||
| Proportional error 5FU | 0.36 | 10.2 | 0.32 | 9.37 | 0.23–0.44 | ||
| Proportional error 5FUH2 | 0.14 | 8.06 | 0.14 | 9.61 | 0.10–0.18 | ||
| Proportional error total WBC count | 0.08 | 8.70 | 0.08 | 8.97 | 0.06–0.11 | ||
RSE relative standard error, CI confidence interval, CL5FU total clearance of 5FU, VC,5FU 5FU central volume of distribution, VP,5FU 5FU peripheral volume of distribution, Q intercompartmental clearance, BSA body surface area, Fm fraction of 5FU converted to 5FUH2, CL5FUH2 clearance of 5FUH2, CIRC0 baseline leukocyte count, MTT mean transit time, Slopecomb slope parameter for combination therapy with cisplatin, Slopemono slope parameter for 5FU monotherapy, The “Slope” parameter represents the relationship between effect and drug concentration into bone marrow (Edrug = slope × Cp), Cp plasma concentration, IIV interindividual variability, RUV residual unexplained variability, CV coefficient of variation
aFractional change in CL per m2 difference from median BSA value
bCalculated by obtaining time integral of drug concentrations using an additional compartment in NONMEM