Nonclinical PK/PD cutoff Value Reviewer’s Comment:

The Agency’s clinical pharmacology team determined that there was a difference in the target
attainment that was possible under fed versus fasting conditions. This difference was notable at a cut-off
value of MIC 0.125 mcg/mL. Above that value, the exposures under fed conditions could not support the
breakpoints. There was residual uncertainty in the cut-off values under fasting conditions and therefore
reliance was on the clinical cut-off values and in vitro antimicrobial activity of lefamulin for
determination of breakpoints. The Applicant’s breakpoint proposal was different than the Agency’s, and
one reason is because of differences in determination of the nonclinical PK/PD cut-off values for
susceptibility. The Agency’s clinical pharmacology team further reevaluated probability of target
attainment in epithelial lining fluid (ELF) versus plasma and the effect of protein binding. See the
Agency’s clinical pharmacology review for further details.