1944. Population Pharmacokinetic (PPK) Analysis for Lefamulin Using Phase 1 Data and Assessment of Optimal PK Sampling Strategies (OSS) for a Phase 3 Community-Acquired Bacterial Pneumonia (CABP) Study
Session: Poster Abstract Session: Antimicrobial Pharmacokinetics and Pharmacodynamics
Saturday, October 29, 2016
Room: Poster Hall
Background: Lefamulin, a semi-synthetic intravenous (IV) and oral (PO) pleuromutilin antibiotic with activity against pathogens commonly associated with CABP, including multi-drug resistant S. pneumoniae and S. aureus,is currently in Phase 3 development for the treatment of patients with CABP. The objectives of these analyses were to refine a previously-developed PPK model using Phase 1 data and to assess OSS for implementation in Phase 3.

Methods: Lefamulin PK data were obtained from healthy subjects who received single 150 mg IV and 600 mg PO lefamulin doses under fed and fasted conditions. Using parameter estimates from the final PPK model, lefamulin AUC0-24 at steady-state (AUC0-24,SS) was determined for 2000 simulated patients after administration of lefamulin 600 mg PO Q12h for 5 days. Multiple linear regression-based OSS determination was then conducted to identify informative sampling times for predicting AUC0-24,SS. OSS were evaluated with fixed sampling times or sampling windows in all simulated patients. A mix of different scenarios (i.e., an unbalanced design) among simulated patients was also evaluated.

Results: The PPK analysis dataset contained 959 lefamulin plasma concentrations from 20 (8 female and 12 male) fasted and fed healthy subjects. A three-compartment model with nonlinear protein binding and two parallel first-order absorption processes provided precise and unbiased estimates of lefamulin plasma exposure (Figure 1). Covariate analyses demonstrated that the absorption rate was slower and bioavailability was decreased after a high fat/high calorie meal compared to the fasted condition. OSS assessments demonstrated that a minimum of 4 samples at fixed times provided accurate AUC0-24,SS estimates, regardless of fed or fasted status. Additionally, a 3- or 4-sample scheme or an unbalanced design, each based on sampling windows, provided acceptably precise estimates of AUC0-24,SS under fed and fasted conditions (R2>0.77, Figure 2).

Conclusion: The refined PPK model provided precise and unbiased fits to lefamulin PK data after IV and PO administration. Application of this model identified an OSS which should allow for reliable AUC0-24,SS estimates for patients who received lefamulin 600 mg PO Q12h in a Phase 3 CABP trial. 

 

Li Zhang, M.D., Ph.D.1, Sujata Bhavnani, Pharm.D., M.S.1, Paul G. Ambrose, Pharm.D., FIDSA1, Wolfgang W. Wicha, M.S.2, Steve Gelone, Pharm.D.3 and Christopher M. Rubino, Pharm.D.1, (1)Institute for Clinical Pharmacodynamics, Schenectady, NY, (2)Nabriva Therapeutics AG, Vienna, Austria, (3)Nabriva Therapeutics AG, King of Prussia, PA

Disclosures:

L. Zhang, Nabriva Therapeutics AG: Research Contractor , Research support

S. Bhavnani, Nabriva Therapeutics AG: Research Contractor , Research support

P. G. Ambrose, Nabriva Therapeutics AG: Research Contractor , Research support

W. W. Wicha, Nabriva Therapeutics AG: Employee and Shareholder , Salary and Stock options

S. Gelone, Nabriva Therapeutics AG: Employee and Shareholder , Salary and Stock options

C. M. Rubino, Nabriva Therapeutics AG: Research Contractor , Research support

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