Monte Carlo simulations in support of NXL103 dose selection
Abstract number: P1597
Felices M., Gualano V., Tarral A., Sable C., Merdjan H.
Objectives: NXL103 is a novel oral streptogramin, a combination of linopristin (PI) and flopristin (PII) with activity against S. aureus (SA), including methicillin-resistant (MR) strains, S. pneumoniae (SP), including multidrug resistant strains, H. influenzae, and atypical pathogens. The study objective was to predict the probability of target attainment (PTA) for various combinations of dose regimen and MIC values, by using Monte Carlo (MC) simulations.
Methods: In murine models of thigh and lung infections, NXL103 efficacy demonstrated to be best correlated with the AUC24/MIC ratios of 14 and 32 for SA and SP, respectively. The MIC90 values for a contemporary population of SA and SP isolates were 0.25 and 0.5 microg/ml, respectively. As a result, the selected MIC values were 0.25, 0.5 and 1 microg/ml. The simulated dose regimens were 300, 500, 600 or 1000 mg BID, and 250, 500 or 600 mg TID. PI and PII were in a 5:7 dose ratio in the above NXL103 doses. Given the beneficial food-effect on NXL103 bioavailability, it was assumed that either all doses were given with food, or either one, or two, or three daily doses (TID only) were given fasted. For each dosing condition, 10,000 replicates of PI and PII AUCs were simulated from validated population pharmacokinetic models. The steady state AUC24 of NXL103 was derived, together with its distribution. Ultimately, the PTA was calculated as the proportion of the AUC24/MIC distribution above a given target. All calculations were done with SAS.
Results: The PTA is tabulated for the various dose regimens given in fed conditions and for both target AUC24/MIC values. Efficacious daily doses should not be changed if a maximum of one dose per day is taken fasted. These results specifically apply to the current tablet formulation of oral NXL103 containing PI and PII in a 5:7 dose ratio (ca 42:58).
Conclusion: A 500 mg BID dose regimen should be efficacious against SA with MIC values of 0.25 and 0.50 microg/ml, including CA-MRSA and HA-MRSA strains. Higher doses may be required to treat infections caused by SP strains.
|Session name:||Abstracts 20th European Congress of Clinical Microbiology and Infectious Diseases|
|Location:||Vienna, Austria, 10 - 13 April 2010|
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