TABLE 10.
Population PK and PD parameter estimates for clinical trial simulationsa
| Parameter | Final model value |
||
|---|---|---|---|
| Estimate (%SE) | Bootstrap (1,000 runs) |
||
| Median estimate | 95% CI | ||
| Fixed effects | |||
| Pharmacokinetics | |||
| CL/F (liters/h) | 3.69 (3) | 3.7 | 3.48–3.91 |
| V2/F (liters) | 14.9 (30) | 15.9 | 9.77–24.8 |
| Q/F (liters/h) | 63 (15) | 63.1 | 47.7–81.8 |
| V3/F (liters) | 150 (6) | 149 | 132–163 |
| Absorption lag time (h) | 0.235 (3) | 0.24 | 0.22–0.24 |
| Ka (h−1) | 0.925 (23) | 0.95 | 0.65–1.37 |
| Bacterial growth dynamicsb | |||
| knetF (h−1) | 0.0272 (FIX) | ||
| knetS (h−1) | 0.00068 (FIX) | ||
| Bmax (log10 CFU/sputum) | 6.2 (FIX) | ||
| Inoculum in patient (log10 CFU/sputum) | 2 (FIX) | ||
| Drug effects | |||
| Emax-F (h−1) | 0.052 (FIX)b | ||
| Emax-S (h−1) | 0.0037 (FIX)b | ||
| EC50-F (mg/liter) | 0.0147 (FIX)c | ||
| EC50-S (mg/liter) | 0.03 (FIX)c | ||
| Random effects | |||
| IIV1 CL/F | 16.1 (22) | 15.8 | 11.8–20 |
| IIV1 V2/F | 111 (37) | 107 | 70.7–140 |
| IIV1 Q/F | 27.3 (37) | 26.5 | 17.3–40 |
| IIV1 V3/F | 23.3 (30) | 22.9 | 17.3–31.6 |
| Residual variability (%) (Prop) | 12.9 (16) | 12.6 | 10–14.1 |
Based on available data (no covariates were tested). knetF, net growth rate of a fast-growing population; knetS, net growth rate of a slow-growing population. IIV, interindividual variability; Prop, proportionality; FIX, fixed parameter.
The SE for the inoculum and Bmax (bacterial carrying capacity in sputum samples) could not be calculated as these are fixed parameters. SE for net growth rates were <1%.
Fixed to estimated values from acute and chronic mouse infection models. The SE for Emax-F (maximum killing rate against a fast-growing population) and Emax-S (maximum killing rate against a slow-growing population), were 2% and 5%, respectively, calculated as EC50,mouse × (plasma unbound fraction656,mouse/plasma unbound fraction656,human), with the EC50-F (potency [50% effective concentration] against a fast-growing population) and EC50-S (potency against a slow-growing population) in mouse being 0.0156 mg/liter (SE = 13%) and 0.0317 mg/liter (SE = 23%), respectively. Unbound fractions of GSK3036656 in mouse and humans were experimentally determined to be 0.792 and 0.838, respectively.