Pharmacokinetics, safety and population pharmacokinetics/pharmacodynamics analysis of meropenem-vaborbactam in Chinese healthy participants.

BACKGROUND: Meropenem-vaborbactam is a fixed-dose β-lactam/β-lactamase inhibitor combination active against carbapenem-resistant Enterobacterales (CRE), especially Klebsiella pneumoniae carbapenemase (KPC)-producing CRE. This study evaluated its pharmacokinetics (PK), safety, and tolerability in Chinese participants, and performed population pharmacokinetics/pharmacodynamics (PK/PD) analysis using in vitro data to assess the suitability of the standard dosing regimen for treating CRE infections in China. METHODS: This single-center, open-label study included 20 healthy participants divided into two groups receiving meropenem-vaborbactam (1:1) at 1 g/1 g or 2 g/2 g via 3-h infusion. Plasma and urine concentrations of meropenem, its open-ring metabolite, and vaborbactam were analyzed using a validated liquid chromatography-tandem mass spectrometry method. PK analysis was conducted using WinNonlin. Monte Carlo simulations were used to evaluate the 1 g/1 g and 2 g/2 g regimens administered every 8 h as 3-h intravenous infusions. For the standard 2 g/2 g regimen, the impact of extending the infusion duration from 3 to 4 h was further evaluated based on the FDA-recommended PK/PD target. RESULTS: Plasma concentrations of meropenem, its open-ring metabolite, and vaborbactam peaked immediately after infusion, with rapid distribution and elimination. Exposure increased proportionally with dose, and almost no accumulation was observed after repeated 8-hourly dosing. Most meropenem (68.5%-77.0%) and nearly all vaborbactam were excreted unchanged in urine. Both single and multiple doses were well tolerated, with no severe or serious adverse events. In addition, PK/PD analysis showed that, for CRE isolates, the standard 2 g/2 g every 8 h regimen with a 3-h intravenous infusion achieved ≥90% probability of target attainment for meropenem (45% fT > MIC) at MIC values up to 8 mg/L. The corresponding cumulative fraction of response ranged from 98.67 to 100% across ESBL-producing and KPC-producing Enterobacterales, including bla KPC variants resistant to ceftazidime-avibactam. CONCLUSION: The standard meropenem-vaborbactam regimen (2 g/2 g every 8 h, 3-h intravenous infusion) demonstrated favorable PK and safety profiles, with PK/PD analyses supporting the appropriateness of the standard regimen in Chinese participants, consistent with global findings. These results provide PK/PD support for the standard regimen and warrant further evaluation in Chinese patients with CRE infections.