Table 1.
Final parameter estimates for preclinical PK‐PD model fitted to mouse 5‐FU plasma and tECF disposition and efficacy studies
| Parameters | Unit | Estimate ± SE | IIV (% CV) |
|---|---|---|---|
| Plasma PK study | |||
| Maximum plasma 5‐FU elimination rate (Vmax,plasma,m) | μmol/hr/kg | 2040 ± 239 | 12.2 |
| Michaelis–Menten constant for plasma 5‐FU elimination (Km,plasma,m) | μM | 125 ± 22 | NE |
| Volume of central compartment (V1,m) | L/kg | 0.962 ± 0.691 | 22.1 |
| Intercompartmental clearance (Qm) | L/hr/kg | 1.67 ± 1.03 | 31.1 |
| Volume of peripheral compartment (V2,m) | L/kg | 0.332 ± 0.50 | NE |
| Residual variability for 5‐FU plasma concentrations (σplasma, prop) | % CV | 30.7 | |
| Tumor microdialysis study | |||
| Rate constant for 5‐FU movement from plasma to tECF (K13,m) | 1/hr | 0.0043 ± 0.001 | 7.8 |
| Rate constant for 5‐FU movement from tECF to plasma (K31,m) | 1/hr | 3.24 ± 0.58 | 26.1 |
| 5‐FU fraction unbound in mouse plasma (fu,m) | 0.37 FIX | NE | |
| Volume of tECF compartment (V3,m) | L/hr | 0.001 FIX | NE |
| Rate parameter for intratumoral 5‐FU disposition (K34,m) | 1/hr | 1.82 ± 0.30 | NE |
| Rate parameter for intratumoral 5‐FU disposition (K43,m) | 1/hr | 0.334 ± 0.077 | NE |
| Maximum tumor 5‐FU elimination rate (Vmax,tumor,m) | μmol/hr/kg | 0.0063 ± 0.004 | NE |
| Michaelis–Menten constant for tumor 5‐FU elimination (Km,tumor,m) | μM | 0.012 ± 0.023 | NE |
| Residual variability for 5‐FU plasma concentrations (σplasma, prop) | % CV | 35.9 | |
| Residual variability for 5‐FU tumor concentrations (σtECF, prop) | % CV | 27.9 | |
| Efficacy study | |||
| Exponential tumor growth parameter ( ) for experiment one | 1/hr | 0.158 (0.079–0.337)a | 40.6 |
| Linear covariate effect on for experiments two and three ( ) | 1/hr | 0.102 (0.031–0.287)a | |
| Linear tumor growth parameter (Klin,m) | 1/hr | 214,000 (66,700–1,480,000)a | NE |
| Constant related to switching tumor growth from exponential to linear (Ψm) | 0.0936 (0.085–0.104)a | NE | |
| Maximum 5‐FU tumor inhibitory effect (Kmax,m) | 1/hr | 0.658 (0.316–1.134)a | NE |
| 5‐FU tECF concentration producing half the maximum tumor inhibitory effect (IC50,m) | μM | 2.12 (0.28–5.84)a | 30.4 |
| Hill coefficient (Hm) | 1.22 (0.64–1.89)a | NE | |
| Rate constant transit tumor compartment (Kdel,m) | 1/hr | 0.946 (0.124–1.950)a | NE |
| Residual variability for tumor growth (σefficacy, prop) | % CV | 37.0 | |
5‐FU, 5‐fluorouracil; CV, coefficient of variation; FIX, value fixed during estimation; IIV, interindividual variability; NE, not estimated; PK‐PD, pharmacokinetic‐pharmacodynamic; tECF, tumor extracellular fluid concentration.
a
aValues represent 2.5th and 97.5th percentile of bootstrap‐derived parameter estimates.