TABLE 2.
Target attainment in plasma and lungs of the considered compounds at human equivalent doses in terms of hours and relative change between plasma and lungs.
| Comp. | RPT | RIF | BDQ | DEL | PRE | INH | OPC | G286 (*) | PZA | MOX | EMB | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| MIC50 | Plasma | 24 (24–24) | 24 (24–24) | 24 (24–24) | 24 (24–24) | 24 (21.7–24) | 11.5 (7.2–18.3) | 11.6 (8.1–17.2) | 10.2 (7.2–14.3) | 5.7 (3.7–9) | 4.9 (3.6–6.9) | 5.5 (3.8–7.9) |
| Lung | 24 (24–24) | 24 (24–24) | 24 (24–24) | 24 (24–24) | 24 (24–24) | 11.6 (7.3–18.6) | 12.4 (8.6–18.4) | 10.6 (7.5–15) | 4.8 (3.1–7.6) | 5.6 (4.1–7.8) | 8.2 (6–11.8) | |
| ∆ (%) | 0 | 0 | 0 | 0 | 0 | 0.87 | 6.9 | 3.92 | −15.79 | 14.29 | 49.09 | |
| MBC90 | Plasma | 24 (24–24) | 24 (24–24) | 0 (0–0) | 24 (24–24) | 24 (21.3–24) | 11.3 (7.1–18.1) | 11.6 (8.1–17.2) | NA | 6.2 (4–9.8) | 4.6 (3.4–6.4) | 6 (4.2–8.6) |
| Lung | 24 (24–24) | 24 (22.9–24) | 24 (21.8–24) | 24 (24–24) | 24 (24–24) | 11.5 (7.2–18.3) | 12.4 (8.6–18.4) | NA | 5.3 (3.4–8.4) | 5.3 (3.9–7.4) | 8.7 (6.3–12.5) | |
| ∆(%) | 0 | 0 | inf | 0 | 0 | 1.77 | 6.9 | NA | −14.52 | 15.22 | 45 | |
| MacroIC90 | Plasma | 24 (24–24) | 24 (20.3–24) | 24 (21–24) | 24 (22.4–24) | 24 (19–24) | 12.2 (7.6–19.5) | 17.4 (11.8–24) | NA | 9 (5.8–14.3) | 3.2 (2.4–4.6) | 2.7 (1.3–4.2) |
| Lung | 24 (24–24) | 23.6 (16.8–24) | 24 (24–24) | 24 (24–24) | 24 (22.4–24) | 12.3 (7.7–19.7) | 18.1 (12.3–24) | NA | 8.2 (5.2–12.9) | 3.9 (2.9–5.5) | 5.7 (4–8.2) | |
| ∆(%) | 0 | −1.66 | 0 | 0 | 0 | 0.82 | 4.02 | NA | −8.89 | 21.88 | 111.11 | |
| WCC90 | Plasma | 24 (24–24) | 22.8 (15.3–24) | 0 (0–5.60) | NA | 12.6 (8.3–19.4) | 1.7 (0.9–2.9) | NA | NA | 5.8 (3.7–9.1) | 1.9 (1.3–2.9) | 0 (0–0) |
| Lung | 24 (24–24) | 17.10 (11.2–24) | 24 (24–24) | NA | 18.4 (12.6–24) | 1.9 (1.1–3.1) | NA | NA | 4.9 (31–7.7) | 2.8 (2–3.9) | 2.4 (1.1–3.8) | |
| ∆ (%) | 0 | −25 | inf | NA | 47.62 | 11.76 | NA | NA | −15.52 | 47.37 | inf |
The table shows the median time in which the compounds are above the PD metrics and the corresponding five and ninety-five percentiles values computed from the virtual population. NA: not available; inf: result of the relative error formula when the baseline is 0. For GSK-2556286, only MIC90 was available and has been used in place of the MIC50 for this analysis. Abbreviations: RPT—rifapentine; RIF—rifampicin; BDQ—bedaquiline; DEL—delamanid; PRE—pretomanid; INH—isoniazid; OPC - OPC-167832; G286 - GSK2556286; PZA—pyrazinamide; MOX—moxifloxacin; EMB—ethambutol; MIC50 - minimum inhibitory concentration to reduce bacterial growth by 50%; MBC90 - the minimum bactericidal concentration to kill 90% viable bacteria under aerobic, nutrient-rich conditions; MacroIC90 - the minimum concentration required to inhibit 90% growth in macrophage; WCC90 - minimum bactericidal concentration achieving a one-log kill of non-replicating bacteria under hypoxic, nutrient-rich conditions; Comp—compartment.