TABLE 2.
Summary of key plasma PK parameters in noncompartmental analysis by day, study drug, and cohorta
| Drug and cohortb | Statistic summary | Day 1 |
Day 7 |
|||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
Cmax mg/L |
Cmin (Css) (mg/L) | AUC0–tau (mg*h/L) | Cmax (mg/L) | AUC0–tau (mg*h/L) | AUCinf (mg*h/L) | t1/2 (h) | Kel (h-1) | Vss (L) | CL (L/h) | RAUC0–tau | ||
| Ceftazidime | ||||||||||||
| Cohort 1 | N | 8 | 8 | 8 | 8 | 8 | 8 | 8 | 8 | 8 | 8 | 8 |
| Geometric mean | 66.4 | 5.4 | 221.0 | 62.5 | 216.0 | 234.0 | 2.6 | 0.27 | 19.6 | 8.5 | 0.98 | |
| Geometric CV (%) | 24.5 | 23.0 | 16.4 | 19.2 | 12.20 | 11.1 | 4.9 | 4.9 | 19.5 | 11.1 | 13.1 | |
| Cohort 2 | N | 8 | 8 | NR | 8 | 8 | 8 | 8 | 8 | 8 | 8 | NR |
| Geometric mean | 70.3 | 23.3 | NR | 31.2 | 223.0 | 302.0 | 2.6 | 0.27 | 12.2 | 6.7 | NR | |
| Geometric CV (%) | 17.3 | 90.4 | NR | 22.1 | 20.8 | 21.4 | 21.2 | 21.2 | 24.9 | 22.3 | NR | |
| Cohort 5c | N | 8 | 8 | 8 | 4 | 4 | 4 | 4 | 4 | 4 | 4 | 4 |
| Geometric mean | 81.0 | 5.9 | 253.0 | 87.5 | 260.0 | 276.0 | 2.6 | 0.27 | 14.2 | 7.2 | 0.95 | |
| Geometric CV (%) | 21.7 | 35.2 | 13.8 | 13.6 | 10.8 | 9.7 | 4.3 | 4.3 | 22.2 | 9.7 | 4.8 | |
| Cohort 6 | N | 8 | 8 | 8 | 8 | 8 | 8 | 8 | 8 | 8 | 8 | 8 |
| Geometric mean | 69.2 | 6.1 | 239.0 | 69.4 | 228.0 | 247.0 | 2.6 | 0.27 | 18.8 | 8.1 | 0.95 | |
| Geometric CV (%) | 19.8 | 27.0 | 15.0 | 12.1 | 12.4 | 11.5 | 9.3 | 9.3 | 21.0 | 11.5 | 5.2 | |
| Avibactam | ||||||||||||
| Cohort 1 | N | 8 | 8 | 8 | 8 | 8 | 8 | 8 | 8 | 8 | 8 | 8 |
| Geometric mean | 12.2 | 0.48 | 35.4 | 10.5 | 30.6 | 31.9 | 2.5 | 0.27 | 25.5 | 15.7 | 0.87 | |
| Geometric CV (%) | 21.6 | 41.6 | 16.2 | 22.9 | 12.1 | 11.7 | 5.8 | 5.8 | 20.6 | 11.7 | 14.5 | |
| Cohort 2d | N | 8 | 8 | NR | 8 | 8 | 7 | 7 | 7 | 7 | 7 | NR |
| Geometric mean | 12.9 | 3.5 | NR | 4.5 | 32.8 | 41.8 | 2.2 | 0.31 | 16.9 | 12.0 | NR | |
| Geometric CV (%) | 17.5 | 113.0 | NR | 17.7 | 17.8 | 17.7 | 12.5 | 12.5 | 26.3 | 18.6 | NR | |
| Cohort 5c | N | 8 | 8 | 8 | 4 | 4 | 4 | 4 | 4 | 4 | 4 | 4 |
| Geometric mean | 15.5 | 0.68 | 43.4 | 14.1 | 37.5 | 38.9 | 2.5 | 0.28 | 18.1 | 12.9 | 0.8 | |
| Geometric CV (%) | 19.2 | 44.2 | 17.2 | 12.1 | 12.0 | 12.0 | 6.1 | 6.1 | 26.5 | 12.0 | 3.8 | |
| Cohort 6 | N | 8 | 8 | 8 | 8 | 8 | 8 | 8 | 8 | 8 | 8 | 8 |
| Geometric mean | 14.0 | 0.67 | 41.8 | 12.7 | 34.0 | 35.6 | 2.4 | 0.28 | 23.6 | 14.0 | 0.8 | |
| Geometric CV (%) | 22.1 | 40.0 | 18.7 | 16.8 | 18.7 | 18.6 | 8.6 | 8.6 | 26.1 | 18.6 | 7.5 | |
| Aztreonam | ||||||||||||
| Cohort 3 | N | 8 | 8 | 8 | 8 | 8 | 8 | 8 | 8 | 8 | 8 | 8 |
| Geometric mean | 88.5 | 13.7 | 264.0 | 77.9 | 236.0 | 261.0 | 1.6 | 0.44 | 14.2 | 7.7 | 0.89 | |
| Geometric CV (%) | 12.6 | 20.9 | 14.0 | 12.0 | 13.2 | 14.4 | 12.1 | 12.1 | 12.4 | 14.4 | 8.2 | |
| Cohort 4 | N | 8 | 8 | NR | NR | NR | NR | NR | NR | NR | NR | NR |
| Geometric mean | 93.7 | 58.5 | NR | NR | NR | NR | NR | NR | NR | NR | NR | |
| Geometric CV (%) | 5.5 | 11.0 | NR | NR | NR | NR | NR | NR | NR | NR | NR | |
| Cohort 5c | N | 8 | 8 | 8 | 4 | 4 | 4 | 4 | 4 | 4 | 4 | 4 |
| Geometric mean | 70.2 | 13.1 | 219.0 | 74.0 | 221.0 | 244.0 | 1.6 | 0.42 | 11.4 | 6.2 | 0.91 | |
| Geometric CV (%) | 17.4 | 16.3 | 14.7 | 11.7 | 11.1 | 9.42 | 10.7 | 10.7 | 19.9 | 9.4 | 3.9 | |
| Cohort 6 | N | 8 | 8 | 8 | 8 | 8 | 8 | 8 | 8 | 8 | 8 | 8 |
| Geometric mean | 91.9 | 18.5 | 292.0 | 89.0 | 275.0 | 313.0 | 1.8 | 0.39 | 13.5 | 6.4 | 0.94 | |
| Geometric CV (%) | 18.2 | 21.0 | 15.7 | 18.6 | 17.0 | 16.8 | 17.5 | 17.5 | 21.3 | 16.8 | 4.9 | |
Cmax, maximum concentration; Cmin, trough concentration at steady state (present for cohorts 1, 3, 5, and 6); Css, plasma concentration at steady state (presented for cohorts 2 and 4); AUC0–tau, AUC from time zero to tau (tau, 8 hours for ceftazidime and avibactam and 6 hours for aztreonam) after the dose; AUCinf, AUC from time of dosing extrapolated to infinity on day 7; CL, total body clearance; Vss, volume of distribution; t1/2, terminal phase disposition half-life; Kel, terminal elimination rate constant; RAUC: accumulation ratio for day 1 AUC0-tau/day 7 AUC0-tau; NR, not reported.
Drug cohorts: CZA 2.5 g i.v. over 2 h every 8 h (cohort 1); CZA 2.5 g i.v. over 2 h × 1 and then 7.5 g/daily as a continuous infusion (CI) (cohort 2); ATM 2 g i.v. over 2 h every 6 h (cohort 3); ATM 2 g i.v. × 1 and then 8 g/daily as a CI (cohort 4); CZA 2.5 g i.v. over 2 h every 8 h with ATM 1.5 g i.v. over 2 h every 6 h (cohort 5); CZA 2.5 g i.v. over 2 h every 8 h with ATM 2 g i.v. over 2 h every 6 h (cohort 6).
N = 4 due to 4 subjects missing aztreonam doses on day 7 in cohort 5; all day 7 plasma PK data for ATM were excluded from the PK analysis. All subjects in cohort 4 on day 7 for ATM were excluded from the PK analysis due to stopped dosing.
N = 7 due to 1 subject’s Kel being not in acceptance criteria (R2 adjusted < 0.8).