title: Effect of H2 blockade and food on single-dose pharmacokinetics of GSK1322322, a peptide deformylase inhibitor antibacterial.
abstract: GSK1322322 is first in a new class of antibiotics, peptide deformylase inhibitors, and is active against multidrug-resistant respiratory and skin pathogens. Part 1 of this phase 1, randomized, single-dose (1,000 mg) study in 20 healthy volunteers compared the relative bioavailability of three different tablet formulations of GSK1322322 (fast release, intermediate release, and slow release) to that of the previously studied powder-in-bottle formulation to assess the optimal formulation for progression into clinical trials. Part 2 assessed the effect of a high-fat meal and drug interaction with an H2 blocker and an H2 blocker plus vitamin C on the pharmacokinetic profile of GSK1322322. Of the three tablet formulations, fast-release GSK1322322 provided pharmacokinetic profiles similar to those of the powder-in-bottle reference formulation (~93% relative bioavailability) and was selected for progression in part 2. When GSK1322322 was administered with a high-fat meal, the maximum observed plasma concentration (C(max)) was reduced by 20%, and the time to maximum plasma concentration (T(max)) was delayed by 1.9 h. The exposure (area under the concentration-time curve [AUC]) increased by ~20% compared to that in volunteers in the fasted state. Coadministration of GSK1322322 with an H2 blocker resulted in a slight delay in absorption (T(max) ~0.75 h later) and 58 and 38% decreases in the C(max) and AUC0-∞ values, respectively, compared to GSK1322322 alone. This effect was reversed with vitamin C intake (i.e., no delay in T(max) and the C(max) and AUC0-∞ values decreased by only 21 and 12%, respectively). GSK1322322 was generally well tolerated, and most adverse events were mild in intensity during both parts of the study.
authors.affiliation: GlaxoSmithKline, Research Triangle Park, North Carolina, 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; D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D001205:Ascorbic Acid / Q000008:administration & dosage*; D001682:Biological Availability; D018592:Cross-Over Studies; D004347:Drug Interactions; D005260:Female; D018565:Food-Drug Interactions; D006635:Histamine H2 Antagonists / Q000008:administration & dosage*; D006801:Humans; D008297:Male; D013607:Tablets; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D006635:Histamine H2 Antagonists; D013607:Tablets; D000581:Amidohydrolases; C084507:peptide deformylase; D001205:Ascorbic Acid