Methods: Data were obtained from 22 patients with CRE infection in an open-label trial to assess the safety and efficacy of plazomicin versus colistin. Intravenous plazomicin doses of up to 15 mg/kg were infused over 30 min (every 12, 24 or 48 h) using a dosing table considering renal function and use of continuous renal replacement therapy. PK samples were collected on Day 1 and at steady-state. Creatinine clearance (CLcr) was estimated daily. TDM samples were collected on Days 1, 4 and/or 8 (±1 day), and on other days if warranted by patient status. Plazomicin plasma concentrations from TDM samples were used to adjust dose to achieve a steady-state AUC0-24 of ~262 mg/L·h (target range 200 to 400 mg/L·h). A previously-developed PPK model (ECCMID 2013, Abstract P914) was refined after pooling the Phase 3 data with data from 82 healthy subjects and 91 Phase 2 patients with complicated urinary tract infections.
Results: A 3-compartment model with zero-order input and first-order elimination, using time-varying CLcr and patient-specific dialysate and ultrafiltrate flow rates to estimate clearance (CL), described plazomicin PK. Interoccasion variability in plazomicin PK was modest (<11% CV). Residual variability was lower in Phase 3 (21.7% CV) versus Phase 2 patients (37.4% CV). Individual post-hoc CL for Phase 3 patients fell within the expected 90% prediction interval from the previous PPK model (Fig 1). Use of TDM substantially improved AUC0-24 targeting relative to the dosing table (Fig 2).
Conclusion: The plazomicin PPK model predicted CL reasonably well in critically ill patients with CRE infections but the significant PK variability observed suggests that individualized plazomicin dosing is needed to ensure target exposures are achieved. Use of TDM ensures that drug exposures are more often in the target range than can be achieved using only standard dosing. This project has been funded in part under HHS BARDA Contract HHSO100201000046C.
S. A. Van Wart,
M. Trang, Achaogen Inc.: Research Contractor , Research support
L. E. Connolly, Achaogen Inc.: Employee and Shareholder , Salary
C. M. Rubino, Achaogen Inc.: Research Contractor , Research support
A. M. Jubb, Achaogen Inc.: Employee and Shareholder , Salary
S. Bhavnani, Achaogen Inc.: Research Contractor , Research support
V. Riddle, Achaogen Inc.: Consultant , Consulting fee
T. Mizuno, Achaogen Inc.: Consultant , Consulting fee
A. A. Vinks, Achaogen Inc.: Consultant , Consulting fee
A. Forrest, Achaogen Inc.: Research Contractor , Research support
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