1976. Pharmacokinetic-Pharmacodynamic (PK-PD) Target Attainment Analyses to Support Oral Lefamulin Dose Selection in the Treatment of Patients with Community-Acquired Bacterial Pneumonia (CABP)
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 Streptococcus pneumoniae (SP) and Staphylococcus aureus (SA), is currently in Phase 3 development for the treatment of CABP. To provide dose selection support for CABP, an existing population PK (PPK) model, in vitro surveillance and non-clinical PK‑PD data for SP and SA, and Monte Carlo simulation were used to assess probabilities of PK-PD target attainment for lefamulin 600 mg PO q12h.

Methods: Data used included a PPK model for IV and PO (fed and fasted) lefamulin developed using Phase 1 data, PK‑PD targets based on neutropenic murine-lung infection models (ICAAC 2015, Abstr A-037) and lefamulin MIC data for SP and SA isolates from the USA and Europe (Antimicrob Agents Chemother. 57:4489-9445). The PPK model was a 3-compartment model with nonlinear protein binding and 2 parallel first-order absorption processes. Using PK parameter estimates, free-drug plasma concentration-time profiles were generated for 2000 simulated patients following lefamulin 600 mg PO q12h under fed and fasted conditions; Day 1 free-drug AUC0‑24 was calculated. Percent probabilities of PK‑PD target attainment by MIC and overall (i.e., weighted over SP and SA MIC distributions) were determined using median free-drug plasma AUC:MIC ratio targets associated with 1‑ and 2-log10 CFU reductions from baseline for SP and SA.

Results: Percent probabilities of PK‑PD target attainment by MIC for SP (Figure 1) and SA (Figure 2) were similar under fed and fasted conditions at MICs ≤ MIC90. Percent probabilities of attaining free-drug plasma AUC:MIC ratio targets associated with a 1-log10 CFU reduction were 100% at the MIC90 (0.25 and 0.12 mcg/mL for SP and SA, respectively) and ≥95.5% at the MIC99 (0.5 and 0.25 mcg/mL for SP and SA, respectively). For free-drug plasma AUC:MIC ratio targets associated with a 2-log10 CFU reduction, percent probabilities were ≥91.9% at MIC90 values. Overall percent probabilities of attaining free-drug plasma AUC:MIC ratio targets for 1- and 2-log10 CFU reductions of SP or SA were ≥99.4 and ≥91.7%, respectively.

Conclusion: These data provide support for lefamulin 600 mg PO q12h for the treatment of patients with CABP and suggest that doses do not need to be taken under fasted conditions.

Sujata Bhavnani, Pharm.D., M.S.1, Li Zhang, M.D., Ph.D.1, Christopher M. Rubino, Pharm.D.1, Justin C. Bader, Pharm.D., MBA1, Wolfgang W. Wicha, M.S.2, Steve Gelone, Pharm.D.3 and Paul G. Ambrose, Pharm.D., FIDSA1, (1)Institute for Clinical Pharmacodynamics, Schenectady, NY, (2)Nabriva Therapeutics AG, Vienna, Austria, (3)Nabriva Therapeutics AG, King of Prussia, PA

Disclosures:

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

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

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

J. C. Bader, 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

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

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