TABLE 2.
Population PK and PD parameters calculated by fitting the model to the observed data after the oral administration of KM (0.28, 1.4, or 7.0 mg kg−1) along with bootstrap validation.
| Parameters | Unit | Final model | Bootstrap (n = 500) | |||
|---|---|---|---|---|---|---|
| Estimate | %RSE | Mean | Median | 2.5th–97.5th percentiles | ||
| Fixed-effect parameters, θ | ||||||
| K a | h−1 | 11.4 | 15.7 | 12.0 | 11.7 | 5.1–25.9 |
| V 1 | mg mL (kg ng)−1 | 0.075 | 15.8 | 0.073 | 0.072 | 0.045–0.10 |
| Effect of 1.4 mg kg−1 on V 1 | 1.31 | 16.8 | 1.20 | 1.23 | 0.30–1.83 | |
| Effect of 7.0 mg kg−1 on V 1 | 1.42 | 20.2 | 1.42 | 1.39 | 0.77–2.03 | |
| V 2 | mg mL (kg ng)−1 | 0.11 | 24.1 | 0.12 | 0.11 | 0.063–0.21 |
| CL 1 | mg mL (kg ng h)−1 | 0.068 | 12.7 | 0.065 | 0.064 | 0.045–0.090 |
| Glu Effect on CL 1 | −0.20 | −15.1 | −0.21 | −0.19 | −0.66–0.082 | |
| CL 2 | mg mL (kg ng h)−1 | 0.052 | 27.6 | 0.053 | 0.051 | 0.028–0.090 |
| E 0 | g | 25.1 | 1.6 | 25.0 | 25.0 | 23.8–25.9 |
| Glu Effect on E 0 | −0.33 | −3.5 | −0.33 | −0.33 | −0.37–(-0.31) | |
| K eff | — | 6.2 | 10.0 | 6.4 | 6.3 | 5.38–8.30 |
| Effect of 1.4 mg kg−1 on K eff | -0.76 | -12.0 | -0.82 | -0.76 | −1.37–(−0.34) | |
| Effect of 7.0 mg kg−1 on K eff | −2.1 | −9.6 | -2.1 | -2.2 | −2.6–(−1.6) | |
| K e | h−1 | 10.5 | 28.5 | 11.8 | 10.4 | 6.4–25.0 |
| Between-subject variability, ω | ||||||
| K a | % | 443.5 | 19.1 | — | — | — |
| V 1 | % | 96.9 | 18.2 | — | — | — |
| V 2 | % | 258.8 | 3.0 | — | — | — |
| CL 1 | % | 85.1 | 12.6 | — | — | — |
| CL 2 | % | 265.5 | 1.6 | — | — | — |
| Residual variability, σ | ||||||
| Log-additive residual error (C) | % | 0.50 | 6.7 | 0.50 | 0.50 | 0.43–0.56 |
| Log-additive residual error (E) | % | 0.11 | 5.1 | 0.11 | 0.11 | 0.10–0.11 |
Ka, absorption rate constant; C1, KM concentration in the central compartment; C2, KM concentration in the peripheral compartment; V1, central volume of KM distribution; V2, peripheral volume of KM distribution; CL1, systemic clearance rate; CL2, inter-compartmental clearance rate; E, the final effects of KM; E0, the baseline value of the MWT; Keff, slope of linear function in KM effect; Ke, first-order rate constant governing the equilibrium distribution of KM between plasma and the effect compartment; ω: variance of BSV; σ: variance of RV.