Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics of the β-Lactamase Inhibitor Vaborbactam (RPX7009) in Healthy Adult Subjects

Griffith, David C.; Loutit, Jeffery S.; Morgan, Elizabeth E.; Durso, Stephanie; Dudley, Michael N.

doi:10.1128/aac.00568-16

Cited by 69 publications

(68 citation statements)

References 5 publications

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“…Treatment regimens were chosen in order to simulate exposures in humans. Briefly, meropenem administered at 100 mg/kg or 300 mg/kg every 2 h over a 24-h period in mice produces an exposure equivalent to 1 g or 2 g of meropenem administered every 8 h by a 3-h infusion in humans, respectively (12,22). Vaborbactam administered at 6.25 mg/kg, 12.5 mg/kg, 25 mg/kg, 50 mg/kg, and 100 mg/kg every 2 h over a 24-h period in neutropenic mice produces an exposure equivalent to 0.25 g, 0.5 g, 1 g, 2 g, or 4 g of vaborbactam administered every 8 h by a 3-h infusion in humans, respectively (12,22).…”

Section: Methodsmentioning

confidence: 99%

Activity of Meropenem-Vaborbactam in Mouse Models of Infection Due to KPC-Producing Carbapenem-Resistant Enterobacteriaceae

Sabet

Tarazi

Nolan

et al. 2018

Antimicrob Agents Chemother

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Meropenem-vaborbactam (Vabomere) is highly active against Gram-negative pathogens, especially carbapenemase (KPC)-producing, carbapenem-resistant The objective of these studies was to evaluate the efficacy of meropenem alone and in combination with vaborbactam in mouse thigh and lung infection models. Thighs or lungs of neutropenic mice were infected with KPC-producing carbapenem-resistant , with meropenem MICs ranging from ≤0.06 to 8 mg/liter in the presence of 8 mg/liter vaborbactam. Mice were treated with meropenem alone or meropenem in combination with vaborbactam every 2 h for 24 h to provide exposures comparable to 2-g doses of each component in humans. Meropenem administered in combination with vaborbactam produced bacterial killing in all strains tested, while treatment with meropenem alone either produced less than 0.5 log CFU/tissue of bacterial killing or none at all. In the thigh model, 11 strains were treated with the combination of meropenem plus vaborbactam (300 plus 50 mg/kg of body weight). This combination produced from 0.8 to 2.89 logs of bacterial killing compared to untreated controls at the start of treatment. In the lung infection model, two strains were treated with the same dosage regimen of meropenem and vaborbactam. The combination produced more than 1.83 logs of bacterial killing against both strains tested compared to untreated controls at the start of treatment. Overall, these data suggest that meropenem-vaborbactam may have utility in the treatment of infections due to KPC-producing carbapenem-resistant.

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Section: Methodsmentioning

confidence: 99%

Activity of Meropenem-Vaborbactam in Mouse Models of Infection Due to KPC-Producing Carbapenem-Resistant Enterobacteriaceae

Sabet

Tarazi

Nolan

et al. 2018

Antimicrob Agents Chemother

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“…Additionally, a cyclic boronic acid, vaborbactam (formerly RPX7009), has been shown to inhibit certain class A, C, and D β‐lactamases. Currently, vaborbactam, in combination with the β‐lactam meropenem, is demonstrating success in clinical trials as Carbavance® …”

Section: Introductionmentioning

confidence: 99%

Exploring the potential of boronic acids as inhibitors of OXA‐24/40 β‐lactamase

et al. 2017

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b-lactam antibiotics are crucial to the management of bacterial infections in the medical community. Due to overuse and misuse, clinically significant bacteria are now resistant to many commercially available antibiotics. The most widespread resistance mechanism to b-lactams is the expression of b-lactamase enzymes. To overcome b-lactamase mediated resistance, inhibitors were designed to inactivate these enzymes. However, current inhibitors (clavulanic acid, tazobactam, and sulbactam) for b-lactamases also contain the characteristic b-lactam ring, making them susceptible to resistance mechanisms employed by bacteria. This presents a critical need for novel, non-b-lactam inhibitors that can circumvent these resistance mechanisms. The carbapenemhydrolyzing class D b-lactamases (CHDLs) are of particular concern, given that they efficiently hydrolyze potent carbapenem antibiotics. Unfortunately, these enzymes are not inhibited by clinically available b-lactamase inhibitors, nor are they effectively inhibited by the newest, non-b-lactam inhibitor, avibactam. Boronic acids are known transition state analog inhibitors of class A and C blactamases, and are not extensively characterized as inhibitors of class D b-lactamases. Importantly, boronic acids provide a novel way to potentially inhibit class D b-lactamases. Sixteen boronic acids were selected and tested for inhibition of the CHDL OXA-24/40. Several compounds were identified as effective inhibitors of OXA-24/40, with K i values as low as 5 lM. The X-ray crystal structures of OXA-24/40 in complex with BA3, BA4, BA8, and BA16 were determined and revealed the importance of interactions with hydrophobic residues Tyr112 and Trp115. These boronic acids serve as progenitors in optimization efforts of a novel series of inhibitors for class D b-lactamases.

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“…The study was conducted at a clinical research facility in Adelaide, Australia (CMAX, Royal Adelaide Hospital, North Terrace, Adelaide, Australia). The doses of vaborbactam used in this study were selected using information gained from previous nonclinical and clinical experience (11,12). Meropenem is approved in many countries for use at doses of up to 2 g q8h (9).…”

Section: Methodsmentioning

confidence: 99%

Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics of Vaborbactam and Meropenem Alone and in Combination following Single and Multiple Doses in Healthy Adult Subjects

Rubino

Bhavnani

Loutit

et al. 2018

Antimicrob Agents Chemother

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Meropenem-vaborbactam is a fixed combination of the novel β-lactamase inhibitor vaborbactam and the carbapenem antibiotic meropenem, developed for the treatment of serious infections caused by drug-resistant Gram-negative bacteria. The safety, tolerability, and pharmacokinetics (PK) of vaborbactam and meropenem following single and multiple ascending doses of each study drug administered alone or combined were evaluated in 76 healthy adult subjects in a randomized, placebo-controlled, double-blind study. Subjects were enrolled in 1 of 5 dose cohorts (receiving 250 to 2,000 mg vaborbactam and/or 1,000 to 2,000 mg meropenem) alone or in combination. No subjects discontinued the study due to adverse events (AEs), and no serious AEs were observed. The pharmacokinetics of meropenem and vaborbactam were similar when given alone or in combination; all evaluated plasma PK exposure measures (peak plasma concentration, area under the plasma concentration-time curve [AUC] from time zero to the last measurable concentration area under the plasma concentration-time curve, and AUC from time zero to infinity) were similar for the study drugs alone versus those in combination, indicating no pharmacokinetic interaction between meropenem and vaborbactam. Across all treatments, 47 to 64% of an administered meropenem dose and 75 to 95% of vaborbactam was excreted unchanged in the urine over 48 h postdose. Meropenem and vaborbactam, when given alone or in combination, have similar pharmacokinetic properties, with no plasma or urine PK drug-drug interactions, and are well tolerated. These findings supported further clinical investigation of the combination product. (This study is registered at ClinicalTrials.gov under registration no. NCT01897779.).

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Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics of the β-Lactamase Inhibitor Vaborbactam (RPX7009) in Healthy Adult Subjects

Cited by 69 publications

References 5 publications

Activity of Meropenem-Vaborbactam in Mouse Models of Infection Due to KPC-Producing Carbapenem-Resistant Enterobacteriaceae

Activity of Meropenem-Vaborbactam in Mouse Models of Infection Due to KPC-Producing Carbapenem-Resistant Enterobacteriaceae

Exploring the potential of boronic acids as inhibitors of OXA‐24/40 β‐lactamase

Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics of Vaborbactam and Meropenem Alone and in Combination following Single and Multiple Doses in Healthy Adult Subjects

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