Tigecycline pharmacodynamics in the hollow fiber system of -complex lung disease, and the utility of MICs and time-kill studies in drug development.

BACKGROUND

Guideline-based therapy (GBT) drugs for (MAC) lung disease (LD) were chosen in part because they have low MICs. Despite these low MICs, GBT achieves six-month sustained sputum culture conversion in only 43% of patients.

METHODS

First, we co-incubated tigecycline with MAC for seven days in time-kill studies and calculated the exposure mediating 50% of maximal effect (E ) or EC . Next, we performed tigecycline exposure-effect studies in the hollow fiber system of MAC (HFS-MAC) inoculated with the reference ATCC#700898 isolate. Third, we performed an exposure-effect study in the HFS-MAC inoculated with 5 different isolates. Finally, the target exposure (EC ) was used to identify a clinical dose of inhaled tigecycline for MAC-LD in 10,000 subject Monte Carlo experiments (MCE).

RESULTS

In time-kill studies the EC was 0-24h area under the concentration-time curve-to-MIC (AUC /MIC) of 62.24 for extracellular and 0.14 for intracellular MAC (p<0.001). In the HFS-MAC inoculated with ATCC#700898, the EC statistically differed between sampling days by 2,370.7%. However, studies with five different isolates demonstrated a stable and robust day-to-day EC (%CV=18.18%), with an EC AUC /MIC of 33.65. The E was 4.84 log CFU/mL. In MCE, tigecycline inhalational doses of 35-40 mg/day achieved the EC target in >90% of virtual patients, with and an MIC breakpoint of 256 mg/L.

CONCLUSION

Time-kill studies do not inform on PK/PD target exposures or extent of kill. Inclusion of multiple MAC isolates in HFS-MAC studies improves precision of pharmacokinetic/pharmacodynamic parameter estimates. Tigecycline via the inhalational route could contribute to treatment of MAC-LD.