Background: Meropenem-vaborbactam is a broad-spectrum carbapenem-β-lactamase inhibitor combination that is being developed to treat patients with serious gram-negative infections, including those caused by Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae (ENT). PK-PD target attainment analyses were undertaken using Monte Carlo simulation, population PK models, non-clinical PK-PD targets for efficacy, and in vitro surveillance data to provide meropenem-vaborbactam dose selection.
Methods: Four simulated patient populations (n=1000 each) varying by creatinine clearance (CLcr) were generated. Using meropenem and vaborbactam population PK models [Trang M et al. Microbe 2017, P2118], individual post-hoc parameter estimates were generated. Using these estimates, total-drug concentration-time profiles were generated for simulated patients with CLcr of ≥40-150 mL/min, ≥20 to 40 mL/min, ≥10 to 20 mL/min, and ≥0 to 10 mL/min who received meropenem-vaborbactam 2 g - 2 g q8h, 1 g 1 g q8h, 1 g - 1 g q12h, 500 mg - 500 mg q12h, respectively, as a 3-hour infusion. Using protein binding estimates (2 and 33%, respectively), Day 1 free-drug meropenem %T>MIC and vaborbactam AUC:MIC ratio were calculated. Percent probabilities of achieving meropenem %T>MIC targets of 30, 35 and 45% associated with net bacterial stasis, and 1- and 2-log10 CFU reductions from baseline, respectively, and the ratio of vaborbactam AUC to meropenem-vaborbactam MIC associated with net bacterial stasis were evaluated. An algorithm to assess PK-PD target attainment at meropenem and corresponding meropenem-vaborbactam MIC values based on in vitro surveillance data for ENT and KPC-producing ENT was followed. For P. aeruginosa, meropenem %T>MIC targets alone were assessed relative to meropenem-vaborbactam MIC values.
Results: Figures 1 to 3 show high percent probabilities of PK-PD target attainment at or above the upper margins of meropenem-vaborbactam MIC distributions for ENT, KPC-producing ENT, P. aeruginosa were observed across all renal function groups.
Conclusion: These data provide support for meropenem 2 g - vaborbactam 2 g q8h administered as a 3-hour infusion and adjusted dosage regimens for patients with varying degrees of renal impairment.
S. M. Bhavnani,
The Medicines Company:
D. C. Griffith, The Medicine's Company: Employee and Shareholder , Salary
O. Lomovskaya, The Medicine's Company: Employee and Shareholder , Salary
J. P. Hammel, The Medicine's Company: Research Contractor , Research support
J. S. Loutit, The Medicine's Company: Employee and Shareholder , Salary
M. N. Dudley, The Medicine's Company: Employee and Shareholder , Salary
P. G. Ambrose, The Medicine's Company: Research Contractor , Research support
C. M. Rubino, The Medicine's Company: Research Contractor , Research support
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