TABLE 3.
Summary of key urine PK parameters in noncompartmental analysis by day, study drug and cohorta
| Drug and cohortb | Statistic summary | Day 1 |
Day 7 |
|||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Ae0–t (mg) | Ae0–24 (mg) | Fe0–t | Fe0–24 | CLR (L/h) | Ae0–t (mg) | Ae0–24 (mg) | Fe0–t | Fe0–24 | ||
| Ceftazidime | ||||||||||
| Cohort 1 | N | 8 | 8 | 8 | 8 | 8 | 7 | 6 | 7 | 6 |
| Geometric mean | 1,230 | 3,560 | 0.62 | 0.59 | 5.58 | 1,290 | 3,920 | 0.64 | 0.65 | |
| Geometric CV (%) | 18.20 | 13.90 | 18.30 | 13.90 | 22.60 | 31.60 | 27.50 | 31.60 | 27.50 | |
| Cohort 2c | N | 7 | 7 | 7 | 7 | 7 | 8 | 8 | 8 | 8 |
| Geometric mean | 2,110 | 4,690 | 0.53 | 0.59 | 6.77 | 1370 | 4,250 | 0.69 | 0.71 | |
| Geometric CV (%) | 14.60 | 15.10 | 14.30 | 15.00 | 22.00 | 31.20 | 18.00 | 31.20 | 18.30 | |
| Cohort 5 | N | 8 | 8 | 8 | 8 | 8 | 6 | 6 | 6 | 6 |
| Geometric mean | 1,780 | 5,540 | 0.89 | 0.92 | 7.03 | 2,370 | 6,010 | 1.18 | 1.00 | |
| Geometric CV (%) | 7.77 | 4.79 | 7.77 | 4.79 | 14.60 | 32.30 | 17.60 | 32.30 | 17.60 | |
| Cohort 6c | N | 7 | 7 | 7 | 7 | 7 | 8 | 8 | 8 | 8 |
| Geometric mean | 2,120 | 6,070 | 1.06 | 1.01 | 9.07 | 1,770 | 5,820 | 0.89 | 0.97 | |
| Geometric CV (%) | 27.00 | 14.60 | 27.00 | 14.60 | 29.20 | 27.90 | 10.20 | 27.90 | 10.20 | |
| Avibactam | ||||||||||
| Cohort 1c | N | 8 | 8 | 8 | 8 | 8 | 7 | 6 | 7 | 6 |
| Geometric mean | 383 | 1,110 | 0.78 | 0.74 | 10.8 | 363 | 1,160 | 0.73 | 0.78 | |
| Geometric CV (%) | 15.6 | 12.5 | 15.3 | 12.5 | 25.2 | 43.30 | 33.2 | 43.3 | 33.2 | |
| Cohort 2c | N | 7 | 7 | 7 | 7 | 7 | 8 | 8 | 8 | 8 |
| Geometric mean | 599 | 1,300 | 0.60 | 0.65 | 11.4 | 349 | 1,130 | 0.70 | 0.76 | |
| Geometric CV (%) | 17.3 | 18.3 | 17.3 | 18.4 | 20.7 | 30.70 | 18.2 | 30.7 | 18.6 | |
| Cohort 5c | N | 8 | 8 | 8 | 8 | 8 | 6 | 6 | 6 | 6 |
| Geometric mean | 488 | 1,500 | 0.98 | 1.00 | 11.2 | 615 | 1620 | 1.23 | 1.08 | |
| Geometric CV (%) | 8.7 | 5.1 | 8.7 | 5.1 | 18.90 | 35.8 | 17.7 | 35.8 | 17.7 | |
| Cohort 6c | N | 7 | 7 | 7 | 7 | 7 | 8 | 8 | 8 | 8 |
| Geometric mean | 582 | 1,630 | 1.16 | 1.09 | 14.0 | 444 | 1,530 | 0.89 | 1.02 | |
| Geometric CV (%) | 25.1 | 13.3 | 25.1 | 13.3 | 33.2 | 31 | 8.8 | 31.0 | 8.8 | |
| Aztreonam | ||||||||||
| Cohort 3 | N | 8 | 7 | 8 | 7 | 8 | 8 | 7 | 8 | 7 |
| Geometric mean | 924 | 4,630 | 0.46 | 0.58 | 4.2 | 1,100 | 4,540 | 0.55 | 0.57 | |
| Geometric CV (%) | 21.0 | 22.0 | 21.0 | 22.0 | 24.1 | 15.4 | 13.7 | 15.4 | 13.7 | |
| Cohort 4 | N | 8 | 8 | 8 | 8 | 8 | 5 | 4 | 5 | 4 |
| Geometric mean | 1,060 | 4,570 | 0.39 | 0.46 | 3.8 | 1.040 | 3,200 | 0.78 | 0.85 | |
| Geometric CV (%) | 28.6 | 27.2 | 28.1 | 27.2 | 26.6 | 36.0 | 8.1 | 35.9 | 10.7 | |
| Cohort 5 | N | 8 | 8 | 8 | 8 | 8 | 7 | 6 | 7 | 6 |
| Geometric mean | 790 | 4,530 | 0.53 | 0.75 | 4.4 | 1,250 | 3,340 | 0.83 | 0.56 | |
| Geometric CV (%) | 34.8 | 11.4 | 34.8 | 11.4 | 37.4 | 43.0 | 60.9 | 43.0 | 60.9 | |
| Cohort 6 | N | 7 | 7 | 7 | 7 | 7 | 8 | 8 | 8 | 8 |
| Geometric mean | 1,050 | 6,210 | 0.53 | 0.78 | 4.4 | 1,110 | 6,250 | 0.55 | 0.78 | |
| Geometric CV (%) | 13.4 | 12.2 | 13.4 | 12.2 | 23.7 | 51.3 | 10.2 | 51.3 | 10.2 | |
Ae0–t, Cumulative amount excreted into the urine from time of dosing up to time t (t, 8 hours for ceftazidime and avibactam and 4 hours for aztreonam); Fe0–t, the fraction of dose excreted in urine from the time of dosing to time t; CLR, ceftazidime and avibactam, calculated as CLR = Ae0–8/AUC0–8 using the same time interval for urine amount and AUC in plasma; aztreonam, calculated as CLR = Ae0–4/AUC0–4 using the same time interval for urine amount and AUC in plasma.
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 < 8 due to missing the urine collection interval, and the subjects were excluded from the urine PK analysis. For AVI and CAZ, the subjects missing urine collection interval 0 to 4 h and 4 to 8 h were excluded from the urine PK analysis, which included one subject in cohort 1 missing the day 6 Ae0–4, one subject in cohort 2 missing the day 1 Ae0–4, one subject in cohort 5 missing the day 6 Ae4–8, another subject in cohort 5 missing the day 6 urine collection data due to study withdrawal, and one subject in cohort 6 missing the day 1 Ae0–4. One subject in cohort 1 was excluded only for the Ae0–24 calculation on day 6 due to missing the 8 to 12 h collection interval. For ATM, the subjects missing the urine collection interval 0 to 4 h included 2 subjects in cohort 4 missing the day 6 Ae0–4, one subject in cohort 4 with no day 6 urine collection due to discordant dosing on day 6, and one subject in cohort 6 with a missing day 1 Ae0–4h. Additionally, one subject in cohort 3 had missing day 1 and day 6 Ae4–8, one subject in cohort 4 had a missing Ae8–12 on day 6, and one subject in cohort 5 had a missing Ae4–8 on day 6, and all were excluded only for the Ae0–24 calculation.