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Pharmacokinetic/pharmacodynamic target attainment analyses to support intravenous and oral lefamulin dose selection for the treatment of patients with community-acquired bacterial pneumonia.


ABSTRACT:

Objectives

Lefamulin is a semi-synthetic intravenous (iv) and oral pleuromutilin antibiotic active against community-acquired bacterial pneumonia (CABP) pathogens. Pharmacokinetic/pharmacodynamic (PK/PD) target attainment analyses were carried out to evaluate lefamulin 150?mg iv q12h and 600?mg orally q12h under fed and fasted conditions for the treatment of patients with CABP.

Methods

The analyses undertaken used a population PK model based on Phase 1 PK data, non-clinical PK/PD targets for efficacy and in vitro surveillance data for Streptococcus pneumoniae (SP) and Staphylococcus aureus (SA), and Monte Carlo simulation. Percentage probabilities of PK/PD target attainment by MIC on day 1 were determined using median total-drug epithelial lining fluid (ELF) and free-drug plasma AUC:MIC ratio targets associated with 1 and 2?log10?cfu reductions from baseline.

Results

Percentage probabilities of attaining the total-drug ELF AUC:MIC ratio target for a 1?log10?cfu reduction from baseline for SP were ?99.2% at the MIC90 of 0.12?mg/L and 96.7%, 82.1% and 96.3% for iv and oral dosing regimens under fed and fasted conditions, respectively, at the MIC99 of 0.25?mg/L. Percentage probabilities of attaining the free-drug plasma AUC:MIC target for the same endpoint at the SP MIC99 were 100% for each regimen. For the SA MIC90 of 0.12?mg/L and AUC:MIC ratio targets for the same endpoint, percentage probabilities were 92.7%-100% for iv and oral dosing regimens.

Conclusions

These data provide support for lefamulin 150?mg iv q12h and 600?mg orally q12h for the treatment of patients with CABP and suggest that doses may not need to be taken under fasted conditions.

SUBMITTER: Bhavnani SM 

PROVIDER: S-EPMC6449570 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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