title: Safety, tolerability and pharmacokinetics of repeat dosing of the antibiotic GSK1322322, a peptide deformylase inhibitor: a randomized placebo-controlled study.
abstract: OBJECTIVE
  GSK1322322 is a potent inhibitor of peptide deformylase, an essential bacterial enzyme required for protein maturation. In this two-part, double-blind, randomized, placebo-controlled, Phase 1 study (study identifier: PDF112668), the safety, tolerability and pharmacokinetics of single and repeat oral-dose GSK1322322 (500-1500 mg) in healthy adult and elderly volunteers were evaluated.
  
  
  METHODS
  Part A included GSK1322322 doses of 500, 750, 1000 and 1500 mg in healthy adults; Part B evaluated 1000 mg of GSK1322322 in healthy elderly volunteers. Volunteers received a single morning dose of a powder-in-bottle formulation of GSK1322322 or placebo on day 1, no dosing on day 2 and twice-daily dosing on days 3-12.
  
  
  RESULTS
  Of 52 enrolled volunteers, 40 and 12 volunteers were treated with GSK1322322 and placebo, respectively. Mean plasma GSK1322322 trough concentration increased with increasing dose and reached steady-state after 2 days of repeat dosing. After single dosing of GSK1322322, maximum plasma concentration and exposure (AUC) were dose proportional from 500 to 1500 mg. However, after repeat dosing, AUC values at steady-state increased slightly more than proportionally, possibly because of a slightly longer terminal elimination t&frac12; after repeat dosing (compared with single-dose t&frac12;) at higher doses (1000 and 1500 mg). There was no age effect or diurnal variation in the GSK1322322 pharmacokinetic profile. GSK1322322 was generally well tolerated-all adverse events were mild to moderate in intensity.
  
  
  CONCLUSIONS
  Repeat oral GSK1322322 (500-1500 mg) for 10 days was well tolerated. These data warrant further clinical investigation of GSK1322322.
authors.affiliation: GlaxoSmithKline, 5 Moore Dr., Research Triangle Park, NC 27709, USA. odin.j.naderer@gsk.com
authors.forename: Odin J
authors.initials: OJ
authors.lastname: Naderer
authors.forename: Etienne
authors.initials: E
authors.lastname: Dumont
authors.forename: John
authors.initials: J
authors.lastname: Zhu
authors.forename: Milena
authors.initials: M
authors.lastname: Kurtinecz
authors.forename: Lori S
authors.initials: LS
authors.lastname: Jones
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D004311:Double-Blind Method; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D010919:Placebos / Q000008:administration & dosage; D010949:Plasma / Q000737:chemistry; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; C583947:GSK1322322; D006877:Hydroxamic Acids; D010919:Placebos
keywords: elderly; peptide deformylase inhibitors; pharmacokinetics; repeat dosing; steady-state