Pharmacokinetics/Pharmacodynamics of Vaborbactam, a Novel Beta-Lactamase Inhibitor, in Combination with Meropenem

Abstract

Vaborbactam is a novel beta-lactamase inhibitor with activity against important beta-lactamases, in particular, serine carbapenemases, and is currently approved in combination with meropenem as Vabomere for the treatment of complicated urinary tract infections, including pyelonephritis. This combination is highly active against Gramnegative pathogens, especially Klebsiella pneumoniae carbapenemase (KPC)-producing carbapenem-resistant Enterobacteriaceae. The objective of these studies was to evaluate vaborbactam pharmacokinetics (PK) and pharmacodynamics (PD) relationships for efficacy in a neutropenic mouse thigh infection model, as well as in an in vitro hollow-fiber infection model, in combination with a fixed exposure of meropenem using KPCcontaining strains of Enterobacteriaceae. For both models, the meropenem dosage regimen was designed to simulate a 2-g dose administered every eight hours (q8h) by 3-h infusion. Vaborbactam dosage regimens were designed to produce a wide range of 24-h areas under the concentration-time curves (AUCs) in the thigh infection model. However, for the hollow-fiber model, the AUCs were limited to values of 192, 320, or 550 mg · h/liter. In both the animal and in vitro models, the PK-PD parameter that best described the antibacterial activity of vaborbactam, when administered in combination with meropenem at exposures equivalent to 2 g dosed q8h by 3-h infusion in humans, was the 24-h free vaborbactam AUC/meropenem-vaborbactam (with vaborbactam at 8 mg/liter) MIC ratio. The magnitude of this ratio for bacteriostasis was 9 to 12 and the magnitude to observe a 1-log kill was 18 to 38. In addition, a magnitude greater than 24 suppressed the development of resistance in the in vitro hollow-fiber model.

Meropenem-Vaborbactam Resistance Selection, Resistance Prevention, and Molecular Mechanisms in Mutants of KPC-Producing Klebsiella pneumoniae

“…The meropenem dose of 2 g infused over 3 h every 8 h was designed to supply concentrations above 8 mg/liter for at least 40% of a dosing interval ( 2 ). Similarly, vaborbactam concentrations of 8 mg/liter are consistent with average plasma concentrations in humans and a free 24-h area under the concentration-time curve of 192 mg · h/liter (8 mg/liter · 24 h) for a 2-g dose administered every 8 h. Phase 1 studies with both components show that these concentrations are readily obtained in humans ( 16 , 25 ) and prevent resistance selection in a hollow-fiber model of infection ( 26 ).…”

Ceftazidime/Avibactam, Meropenem/Vaborbactam, or Both? Clinical and Formulary Considerations

“…Interestingly, when the exposures of vaborbactam were increased to mimic pharmacokinetic data observed in phase 3 trials as opposed to phase 1 trials (median vaborbactam area under the concentration time curve over 24 hours [AUC 24h ] of 550 mg × h/L as opposed to an AUC 24h of 320 mg × h/L), suppression was demonstrated in the isolate with the baseline MIC of 16/8 mg/L [27]. These findings are supported by hollow fiber model data suggesting that a free vaborbactam AUC to meropenem/vaborbactam MIC ratio of >24 is the pharmacodynamic parameter associated with resistance suppression [29]. This target should be easily met with labeled dosing at the MIC breakpoint of 4/8 mg/L.…”

Activity of Simulated Human Dosage Regimens of Meropenem and Vaborbactam against Carbapenem-Resistant Enterobacteriaceae in an In Vitro Hollow-Fiber Model

“…Pharmacokinetic data for meropenem and vaborbactam were obtained from phase 1 studies and the literature (19,20). Following the completion of population pharmacokinetic modeling from phase 3 studies, a dosage regimen of 2 g of meropenem with 2 g of vaborbactam using vaborbactam exposure from patients was also studied (21).…”