Frontiers in pharmacology · 2026
Pharmacokinetics, safety and population pharmacokinetics/pharmacodynamics analysis of meropenem-vaborbactam in Chinese healthy participants.
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Li Wanzhen, Wei Qiong, Chen Mengting, Liu Xiaofen, Guo Beining, Chen Yuancheng, Zhang Qi, Guan Wei, Shen Long, Wang Xiaohui, Li Nanyang, Chen Yan, Li Xin, Hu Yingying, Zhang Jing, Wu Xiaojie
Аннотация
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.
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.