Effect of H2 Blockade and Food on Single-Dose Pharmacokinetics of GSK1322322, a Peptide Deformylase Inhibitor Antibacterial

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 H-2 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 (similar to 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 similar to 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 similar to 0.75 h later) and 58 and 38% decreases in the C-max and AUC(0-infinity) 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 AUC(0-infinity) 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.