1852. Meropenem-Vaborbactam Pharmacokinetic-Pharmacodynamic (PK-PD) Target Attainment Analyses as Support for Dose Selection in Patients with Normal Renal Function and Varying Degrees of Renal Impairment
Session: Poster Abstract Session: Clinical Study with New Antibiotics and Antifungals
Saturday, October 7, 2017
Room: Poster Hall CD

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.

Sujata M. Bhavnani, Pharm.D., M.S.1, Michael Trang, Pharm.D.1, David C. Griffith, B.A.2, Olga Lomovskaya, Ph.D.2, Jeffrey P. Hammel, M.S., B.S.1, Jeffrey S. Loutit, MBChB2, Michael N. Dudley, Pharm.D., FIDSA2, Paul G. Ambrose, Pharm.D., FIDSA1 and Christopher M. Rubino, Pharm.D.1, (1)ICPD, Schenectady, NY, (2)The Medicines Company, San Diego, CA

Disclosures:

S. M. Bhavnani, The Medicines Company: Research Contractor , Research support

M. Trang, The Medicine's Company: Research Contractor , Research support

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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