Penetration of GSK1322322 into Epithelial Lining Fluid and Alveolar Macrophages as Determined by Bronchoalveolar Lavage

Naderer, Odin; Rodvold, Keith A.; Jones, Lori S.; Zhu, John; Bowen, Chester L.; Chen, Liangfu; Dumont, Étienne

doi:10.1128/aac.01836-13

Cited by 11 publications

(14 citation statements)

References 16 publications

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“…Each IV dose was administered to Cohort C at a concentration of 3 mg/mL and a rate of 500 mL/h for 60 minutes. Bronchoalveolar lavage samples were taken from volunteers in Cohort C on day 6 to analyze GSK1322322 concentration in the lung epithelial lining fluid and alveolar macrophages (manuscript in preparation) …”

Section: Methodsmentioning

confidence: 99%

“…Bronchoalveolar lavage samples were taken from volunteers in Cohort C on day 6 to analyze GSK1322322 concentration in the lung epithelial lining fluid and alveolar macrophages (manuscript in preparation). 13 Cohorts D, E, F1, and F2 received IV administration of placebo or a mesylate salt formulation of GSK1322322. Cohort D received a single IV dose of placebo or GSK1322322 2,000 mg on day 1 administered at a concentration of 5 mg/mL and a rate of 400 mL/h for 60 minutes.…”

Section: Study Design and Populationmentioning

confidence: 99%

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Safety, tolerability, and pharmacokinetics of oral and intravenous administration of GSK1322322, a peptide deformylase inhibitor

Naderer

Jones

Zhu

et al. 2013

The Journal of Clinical Pharma

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GSK1322322 is the first in a new class of antibiotics that targets peptide deformylase (PDF), an essential bacterial enzyme required for protein maturation. This randomized, double-blind, placebo-controlled, eight-cohort phase I trial enrolled 62 healthy volunteers to assess safety, tolerability, and pharmacokinetic profiles of GSK1322322. GSK1322322 was administered as a single oral or intravenous (IV) dose, escalating from 500 to 3,000 mg or repeat IV doses escalating from 500 to 1,500 mg twice daily. Upon repeat IV administration, GSK1322322 exhibits linear pharmacokinetics over time upon repeat doses as shown by time-invariant pharmacokinetics. A dose-proportional increase in area under concentration-time curve was observed after single or repeat IV dosing, whereas clearance at steady state remained generally unchanged across doses. There was minimal accumulation of GSK1322322 after repeat IV twice-daily administration. After oral tablet doses of GSK1322322 1,000 and 1,500 mg, absolute bioavailability was 69% and 56%, respectively. GSK1322322 administration at single and repeat IV doses and at supratherapeutic single IV doses of 2,000 and 3,000 mg was associated with mild-to-moderate drug-related adverse events. On the basis of the pharmacokinetics and tolerability demonstrated in this study, GSK1322322 has the potential to become the first-in-class PDF inhibitor for clinical use.

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Section: Methodsmentioning

confidence: 99%

Section: Study Design and Populationmentioning

confidence: 99%

Safety, tolerability, and pharmacokinetics of oral and intravenous administration of GSK1322322, a peptide deformylase inhibitor

Naderer

Jones

Zhu

et al. 2013

The Journal of Clinical Pharma

Self Cite

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“…Although early PDF inhibitors were recognized particularly for their microbiological activity against staphylococci, especially MRSA (203), GSK1322322 also may have useful activity against S. pneumoniae and H. influenzae, with MICs of Յ4 g/ml against these organisms in addition to drug-resistant staphylococci (204,205). Clinical studies in healthy subjects showed good penetration of the inhibitor into epithelial lining fluid and alveolar macrophages (206). Thus, the in vitro microbiological profile and bioavailability in the lung support clinical studies of this drug in respiratory disease.…”

Section: Pdf Inhibitorsmentioning

confidence: 99%

Investigational Antimicrobial Agents of 2013

Pucci

Bush

2013

Clin Microbiol Rev

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SUMMARY New antimicrobial agents are always needed to counteract the resistant pathogens that continue to be selected by current therapeutic regimens. This review provides a survey of known antimicrobial agents that were currently in clinical development in the fall of 2012 and spring of 2013. Data were collected from published literature primarily from 2010 to 2012, meeting abstracts (2011 to 2012), government websites, and company websites when appropriate. Compared to what was reported in previous surveys, a surprising number of new agents are currently in company pipelines, particularly in phase 3 clinical development. Familiar antibacterial classes of the quinolones, tetracyclines, oxazolidinones, glycopeptides, and cephalosporins are represented by entities with enhanced antimicrobial or pharmacological properties. More importantly, compounds of novel chemical structures targeting bacterial pathways not previously exploited are under development. Some of the most promising compounds include novel β-lactamase inhibitor combinations that target many multidrug-resistant Gram-negative bacteria, a critical medical need. Although new antimicrobial agents will continue to be needed to address increasing antibiotic resistance, there are novel agents in development to tackle at least some of the more worrisome pathogens in the current nosocomial setting.

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“…Moreover, plasma and intrapulmonary pharmacokinetic studies with GSK1322322 dosed intravenously twice daily for 4 days showed that its time courses in epithelial lining fluid (ELF) and alveolar macrophages (AM) mirror the plasma concentrationtime profiles. In fact, the area under the concentration-time curve from time 0 to (AUC 0 -) ratios of ELF and AM to total plasma were 1.2 and 2.5, respectively (12). Therefore, GSK1322322 should be active against intracellular L. pneumophila at the con- centrations necessary to achieve efficacy versus the other bacterial respiratory tract pathogens and may be an effective treatment for lower respiratory tract infections caused by this atypical pathogen.…”

mentioning

confidence: 99%

“…West, T. S. Collingwood, K. Aubart, D. J. Holmes, and M. Zalacain, submitted for publication). Therefore, the antibacterial activity shown by GSK1322322 against intracellular L. pneumophila may be due, at least in part, to its potent inhibition of PdfC (G. Van Aller, unpublished results), although its accumulation inside macrophages may also contribute to it (12).…”

mentioning

confidence: 99%

In Vitro and Intracellular Activities of Peptide Deformylase Inhibitor GSK1322322 against Legionella pneumophila Isolates

Dubois¹,

Dubois²,

Martel³

et al. 2015

Antimicrob Agents Chemother

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b GSK1322322, a novel peptide deformylase inhibitor currently in development as an oral and intravenous agent for the treatment of hospitalized community-acquired bacterial pneumonia, showed poor in vitro activity against a panel of 50 Legionella pneumophila strains, with MICs ranging from 1 to 16 g/ml and an MIC 90 of 16 g/ml, but very potent intracellular activity, with the minimum extracellular concentrations capable of inhibiting intracellular proliferation (MIECs) ranging from 0.12 to 2 g/ml and 98% of the strains being inhibited by concentrations of <1 g/ml.T he opportunistic Gram-negative bacterium Legionella pneumophila, which can grow free living or as a facultative intracellular organism in amoebae or human alveolar macrophages, is the major causative agent of Legionnaires' disease, a severe form of pneumonia (1). Although at least 15 serogroups have been identified, L. pneumophila serogroup 1 accounts for more than 80% of the cases worldwide (2). Except in the event of a Legionnaires' disease outbreak, L. pneumophila is treated empirically as part of the therapy used for hospitalized pneumonia, and given the severity of the disease, it is important to ensure that the antibacterial agent to be utilized shows good activity against this pathogen. GSK1322322 is a novel peptide deformylase (PDF) inhibitor with good safety and pharmacokinetic properties (3-5) and is currently in phase II development as an oral and intravenous agent for the treatment of hospitalized community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections. GSK1322322 has demonstrated good antibacterial activity against other causative agents of bacterial pneumonia, such as Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae (6), so it was therefore important to investigate its potency against this atypical pathogen.In order to assess the in vitro activity of GSK1322322, we performed susceptibility studies against 50 L. pneumophila strains: 25 from serogroup 1 and 5 each from serogroups 2, 3, 4, 5, and 6. L. pneumophila isolates were collected from 1992 to 2013, mostly from the human respiratory tract, and grown on buffered charcoal yeast extract (BCYE) agar to produce pure cultures. MIC endpoints were determined by broth microdilution according to Clinical and Laboratory Standards Institute (CLSI) guidelines (7). MIC plates, containing approximately 5 ϫ 10 5 CFU/ml in buffered yeast extract (BYE) broth (with Legionella BCYE growth supplement), were incubated at 35°C in aerobic conditions for 48 h. The MIC was defined as the lowest concentration of antimicrobial agent that completely inhibited visible growth after the appropriate incubation time.GSK1322322 showed variable activities against this panel of 50 L. pneumophila strains, with MICs ranging from 1 to 16 g/ml and MIC 50 and MIC 90 values of 8 and 16 g/ml, respectively (Table 1). No significant differences were observed in the activities of GSK1322322 against strains from different serogroups; 8 g/ml was the most frequent MIC ...

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Penetration of GSK1322322 into Epithelial Lining Fluid and Alveolar Macrophages as Determined by Bronchoalveolar Lavage

Cited by 11 publications

References 16 publications

Safety, tolerability, and pharmacokinetics of oral and intravenous administration of GSK1322322, a peptide deformylase inhibitor

Safety, tolerability, and pharmacokinetics of oral and intravenous administration of GSK1322322, a peptide deformylase inhibitor

Investigational Antimicrobial Agents of 2013

In Vitro and Intracellular Activities of Peptide Deformylase Inhibitor GSK1322322 against Legionella pneumophila Isolates

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