Lefamulin is a semi-synthetic intravenous (IV) and oral pleuromutilin antibiotic entering Phase 3 late-stage clinical development for CABP. Lefamulin is active against pathogens commonly associated with CABP, including multi-drug resistant (MDR) S. pneumoniae (SP), M. pneumoniae, and S. aureus (SA). Using in vitro, non-clinical PK‑PD, and clinical pharmacokinetic (PK) data, PK-PD TA analyses were performed to provide support for the selection of a lefamulin dosing regimen for the treatment of patients with CABP.
Data utilized included a population PK (PPK) model describing the disposition of lefamulin developed using Phase 1 and 2 data, non-clinical PK‑PD targets based on neutropenic murine-lung infection models and MIC data from isolates collected from North America (NA) and the European Union (EU) for lefamulin against SP and SA (SENTRY Program). The PPK model used was a 3-compartment model with first-order elimination with saturable protein binding. Lefamulin concentrations in epithelial lining fluid (ELF) were modeled using first-order rate constants into and out of the ELF compartment. Using the PK parameter estimates, ELF and free-drug plasma concentration-time profiles were generated for 2000 simulated patients following lefamulin 150 mg IV q12h; Day 1 AUC0‑24 values were calculated. Non-clinical ELF and free-plasma AUC:MIC ratio targets (median and second highest) associated with a 1‑log10 CFU reduction from baseline for SP and SA were evaluated. Percent probabilities of PK‑PD TA by MIC value and over MIC distributions for SP and SA were determined.
Percent probabilities of PK‑PD TA by MIC are shown for SP and SA for ELF targets in the Figure. Percent probabilities of attaining median ELF AUC:MIC ratio targets were 97.0% at the MIC99 of 0.5 mg/L for SP and 99.4% at the MIC99 of 0.25 mg/L for SA. For the second highest targets, ≥97.0% PK-PD TA was achieved at MIC90 values for each pathogen. Overall percent probabilities of attaining AUC:MIC ratio targets for SP and SA based on NA and EU MIC data were ≥96.6%. Results based on plasma targets were similar for SP and SA.
Results of these PK‑PD TA analyses for SP and SA provide support for the selection of lefamulin 150 mg IV q12h for the treatment of patients with CABP.
S. M. Bhavnani,
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