Methods: Mechanically ventilated patients with proven or suspected pneumonia received 4-6 doses of 3g TOL/TAZ q8h, adjusted for renal function; safety was evaluated. Plasma PK samples were collected after the first and last doses and PK parameters were calculated using non-compartmental analysis. Probability of target attainment (PTA) was assessed by the percent of patients achieving PK/PD targets: free TOL concentrations above minimum inhibitory concentrations of 4 and 8 µg/mL for ≥40% of the dosing interval (pneumonia breakpoint is 4), free TAZ concentrations above 1 μg/mL for ≥20% of the dosing interval. Baseline creatinine clearance (CrCL) was assessed by Cockroft-Gault (C-G) and compared to urine-derived values.
Results: The 18 patients (11 male) were 21-82 years old with a mean (range) BMI of 26.5 (13.8-55.5) kg/m2 and estimated CrCL of 116 (38-238) mL/min. TOL and TAZ plasma clearances were ~5 and ~16 L/h, respectively; TOL and TAZ steady-state volumes of distribution were ~30 and ~40 L, respectively. The individual percent of time above the PK/PD targets after the first and last doses ranged from 74-100% at 4 μg/mL and 56-100% at 8 μg/mL for TOL and 47-100% at 1 μg/mL for TAZ. There were 27 adverse events (AEs) in 12 patients, with one AE (diarrhea) related to study drug, with no serious AEs reported. Exploratory analyses show a robust correlation between baseline CrCL by C-G and urine (Pearson correlation coefficient 0.626; P=0.0054; P=0.0039, adjusting for weight).
Conclusion: Results from 18 ventilated pneumonia patients demonstrate that 3g TOL/TAZ was well tolerated. All patients achieved the TOL and TAZ PK/PD targets after the first and last doses (100% PTA), suggesting this dose provides adequate exposure from the initiation of therapy. These data support the 3g TOL/TAZ dose and regimen selected for the ongoing Phase 3 NP trial.
D. P. Nicolau, Merck: Investigator and Speaker's Bureau , Research support
J. De Waele, Merck: Speaker's Bureau , Speaker honorarium
J. L. Kuti, None
E. Gadzicki, Merck: Employee , Salary
A. Adedoyin, Merck: Employee , Salary
Z. Zeng, Merck: Employee , Salary
B. Mosquera, Merck: Employee , Salary
R. Saralaya, Merck: Research Contractor , Cytel contracted
E. Rhee, Merck: Employee , Salary
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