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Experimental Therapeutics

Reducing Antibacterial Development Risk for GSK1322322 by Exploring Potential Human Dose Regimens in Nonclinical Efficacy Studies Using Immunocompetent Rats

Jennifer L. Hoover, Christine M. Singley, Philippa Elefante, Peter DeMarsh, Magdalena Zalacain, Stephen Rittenhouse
Jennifer L. Hoover
GlaxoSmithKline, Collegeville, Pennsylvania, USA
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Christine M. Singley
GlaxoSmithKline, Collegeville, Pennsylvania, USA
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Philippa Elefante
GlaxoSmithKline, Collegeville, Pennsylvania, USA
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Peter DeMarsh
GlaxoSmithKline, Collegeville, Pennsylvania, USA
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Magdalena Zalacain
GlaxoSmithKline, Collegeville, Pennsylvania, USA
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Stephen Rittenhouse
GlaxoSmithKline, Collegeville, Pennsylvania, USA
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DOI: 10.1128/AAC.00959-17
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ABSTRACT

Directly testing proposed clinical dosing regimens in nonclinical studies can reduce the risk during the development of novel antibacterial agents. Optimal dosing regimens can be identified in animal models by testing recreated human pharmacokinetic profiles. An example of this approach using continuous intravenous infusions of GSK1322322 in immunocompetent rats to evaluate recreated human exposures from phase I trials in pneumonia models with Streptococcus pneumoniae and Haemophilus influenzae and an abscess model with Staphylococcus aureus is presented. GSK1322322 was administered via continuous intravenous infusion to recreate 1,000- or 1,500-mg oral doses every 12 h in humans. Significant reductions (P ≤ 0.05 for all comparisons) in bacterial numbers compared with those for the baseline controls were observed for S. pneumoniae and H. influenzae (mean log10 reductions, 1.6 to ≥2.7 and 1.8 to 3.3 CFU/lungs, respectively) with the recreated 1,000-mg oral dose. This profile was also efficacious against S. aureus (mean log10 reduction, 1.9 to 2.4 CFU/abscess). There was a nonsignificant trend for improved efficacy against S. aureus with the 1,500-mg oral dose (mean log10 reduction, 2.4 to 3.1 CFU/abscess). These results demonstrate that the human oral 1,000- or 1,500-mg exposure profiles of GSK1322322 recreated in rats were effective against representative community-associated pathogens and supported selection of the 1,500-mg oral dose given every 12 h for a phase II clinical skin infection study. Furthermore, this work exemplifies how the testing of recreated human pharmacokinetic profiles can be incorporated into the development process and serve as an aid for selecting optimal dosing regimens prior to conducting large-scale clinical studies.

FOOTNOTES

    • Received 8 May 2017.
    • Returned for modification 9 June 2017.
    • Accepted 8 August 2017.
    • Accepted manuscript posted online 14 August 2017.
  • Supplemental material for this article may be found at https://doi.org/10.1128/AAC.00959-17 .

  • Copyright © 2017 Hoover et al.

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license .

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Reducing Antibacterial Development Risk for GSK1322322 by Exploring Potential Human Dose Regimens in Nonclinical Efficacy Studies Using Immunocompetent Rats
Jennifer L. Hoover, Christine M. Singley, Philippa Elefante, Peter DeMarsh, Magdalena Zalacain, Stephen Rittenhouse
Antimicrobial Agents and Chemotherapy Oct 2017, 61 (11) e00959-17; DOI: 10.1128/AAC.00959-17

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Reducing Antibacterial Development Risk for GSK1322322 by Exploring Potential Human Dose Regimens in Nonclinical Efficacy Studies Using Immunocompetent Rats
Jennifer L. Hoover, Christine M. Singley, Philippa Elefante, Peter DeMarsh, Magdalena Zalacain, Stephen Rittenhouse
Antimicrobial Agents and Chemotherapy Oct 2017, 61 (11) e00959-17; DOI: 10.1128/AAC.00959-17
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KEYWORDS

Anti-Bacterial Agents
Bridged Bicyclo Compounds, Heterocyclic
Haemophilus influenzae
Hydroxamic Acids
Staphylococcus aureus
Streptococcus pneumoniae
animal model
antibacterial agents
pharmacokinetics
dose optimization
humanized pharmacokinetic profiles
peptide deformylase
dose selection

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