Pharmacokinetic/Pharmacodynamic Evaluation of a Novel Aminomethylcycline Antibiotic, KBP-7072, in the Neutropenic Murine Pneumonia Model against S. aureus and S. pneumoniae [Experimental Therapeutics]

KBP-7072 is a novel aminomethylcycline antibiotic in clinical development for community-acquired pneumonia. The goal of present studies was to determine which pharmacokinetic/pharmacodynamic (PK/PD) magnitude correlated with efficacy in the murine pneumonia infection model against Staphylococcus aureus and Streptococcus pneumoniae. KBP-7072 pharmacokinetic measures were performed in plasma and epithelial lining fluid (ELF) at 4-fold increasing doses from 1-256 mg/kg subcutaneously. Pharmacokinetic parameters were calculated using a noncompartmental model and were linear over the dose range. Penetration into ELF ranged from 82 to 238% when comparing ELF drug concentrations to plasma free drug concentrations. Twenty-four-hour dose-ranging efficacy studies were then performed in the neutropenic murine pneumonia model against 5 S. aureus (3 MRSA, 2 MSSA) and 6 S. pneumoniae (2 Tet^R, 2 Pen^R) strains. KBP-7072 demonstrated potent in vivo activity resulting in a 3-5 log₁₀ kill in CFU burden compared to the start of therapy for all strains. The PK/PD index AUC/MIC corelated well with efficacy (R² 0.80-0.89). Net stasis was achieved at a plasma 24-h free drug AUC/MIC values of 1.13 and 1.41 (24-h ELF AUC/MIC values of 2.01 and 2.50) for S. aureus and S. pneumonia, respectively. One-log₁₀ kill was achieved at 24-h plasma AUC/MIC values of 2.59 and 5.67 (24-h ELF AUC/MIC values 4.22 and 10.08) for S. aureus and S. pneumonia, respectively. A 2-log₁₀ kill was achieved at 24-h plasma AUC/MIC values of 7.16 and 31.14 (24-h ELF AUC/MIC of 8.37 and 42.92) for S. aureus and S. pneumonia, respectively. The results of these experiments will aid in the rational design of dose-finding studies for KBP-7072 in patients with community-acquired bacterial pneumonia (CAP).

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