Abstract

Purpose: NVP-LBM415 is a peptide deformylase inhibitor with in vitro activity against those pathogens commonly associated with community-acquired respiratory tract infections. The purpose of these studies was to determine which pharmacokinetic-pharmacodynamic (PK-PD) measure is most strongly associated with drug response and to examine the relationship between drug exposure and response for NVP-LMB415 against Haemophilus influenzae.

Methods: Two wild-type H. influenzae strains (MIC 2 and 8 μg/mL) were studied. The hollow-fiber system was inoculated with approximately 107-8 CFU/mL in log-phase growth. Simulating human pharmacokinetics (t½ = 2 hours), bacteria were exposed to escalating free drug NVP-LMB415 exposures (AUC ranging from 0 to 200 μg⋅h/L) using a dose fractionation study design and delivering drug every 12 hours, every 24 hours, and by continuous infusion. Serial samples were collected to determine bacterial counts (CFU/mL) and drug concentrations. Drug effect was quantified as the log10 ratio of the 24-hour area under the bacterial growth/kill curves for drug and growth control (log10 ratio = log10 AUCdrug/AUCgrowth control).

Results: Overall, the greatest activity (at 6x MIC) was seen with the continuous infusion regimen (continuous infusion > q12 hours >> q24 hours). Due to the short half-life, dosing q24 hours yielded no net kill compared to baseline. Neither time above MIC, AUC:MIC ratio, nor peak:MIC ratio could co-model the q12 hour and q24 hour regimens with continuous infusion results. Separating these into 2 datasets (q12 plus q24 versus continuous infusion), only the AUC:MIC ratio could adequately describe the continuous infusion results (Emax log10 ratio of -2 at an AUC:MIC ratio ≥ 50). The q12 plus q24 dataset was reasonably fit by the AUC:MIC ratio and percent time above MIC (Emax log10 ratio of -2 to -3 at an AUC:MIC ratio ≥ 120 and percent time above MIC of 50% to 60%, respectively). The peak:MIC ratio was not informative.

Conclusions: For intermittent dosing regimens, percent time above MIC and the AUC:MIC ratio adequately described drug response. Percent time above MIC and the AUC:MIC ratio associated with maximal decline were ≥ 50% to 60% and ≥ 120, respectively. Continuous infusion regimens could not be co-modeled with intermittent regimens, suggesting that neither percent time above MIC nor the AUC:MIC ratio completely described drug effect. Drug effect continued to increase beyond 100% time above MIC. Every 12 hour dosing had more effect than every 24 hour dosing, and would probably be an effective NVP-LBM415 regimen in humans for H. influenzae.

European Congress of Clinical Microbiology and Infectious Disease (ECCMID), Copenhagen, Denmark, April 2005

By Alison K. Meagher, Patrick F. Smith, Alan Forrest, Abayomi Ogundele, Paul G. Ambrose