Tigecycline pharmacodynamics in the hollow fiber system of Mycobacterium avium -complex lung disease, and the utility of MICs and time-kill studies in drug development
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Background
Guideline-based therapy (GBT) drugs for Mycobacterium avium-complex (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 max ) or EC 50 . 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 80 ) 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 50 was 0-24h area under the concentration-time curve-to-MIC (AUC 0-24 /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 50 statistically differed between sampling days by 2,370.7%. However, studies with five different isolates demonstrated a stable and robust day-to-day EC 50 (%CV=18.18%), with an EC 80 AUC 0-24 /MIC of 33.65. The E max was 4.84 log 10 CFU/mL. In MCE, tigecycline inhalational doses of 35-40 mg/day achieved the EC 80 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.
