Reducing antibacterial development risk for GSK1322322 by exploring potential human dose regimens in nonclinical efficacy studies using immunocompetent rats [PublishAheadOfPrint]

Directly testing proposed clinical dosing regimens in nonclinical studies can reduce 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 is presented using continuous intravenous infusions of GSK1322322 in immunocompetent rats to evaluate recreated Phase 1 human exposures in pneumonia models with Streptococcus pneumoniae and Haemophilus influenzae and an abscess model with Staphylococcus aureus. GSK1322322 was administered via continuous intravenous infusion to recreate 1000 or 1500 mg oral doses every 12h in humans. Significant reductions (all p≤0.05) in bacterial numbers were observed versus baseline controls for S. pneumoniae and H. influenzae (mean log₁₀ reductions: 1.6 to ≥2.7 and 1.8 to 3.3 CFU/lung, respectively) with the recreated 1000 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 1500 mg oral dose (mean log₁₀ reduction: 2.4 to 3.1 CFU/abscess). These results demonstrated that the human oral 1000 or 1500 mg exposure profiles of GSK1322322 recreated in rats were effective against representative community-associated pathogens and supported selection of the 1500 mg oral dose given every 12h for a Phase II clinical skin infection study. Furthermore, this work exemplifies how testing recreated human PK 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.

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