1972. Pharmacokinetic-Pharmacodynamic (PK-PD) Target Attainment Analyses for Delafloxacin to Provide Dose Selection Support for 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: Delafloxacin is an investigational IV and PO quinolone with activity against pathogens commonly associated with CABP, including Streptococcus pneumoniae (SP) and Staphylococcus aureus (SA), including methicillin-resistant isolates. To provide support for a delafloxacin IV to PO dosing regimen to treat patients with CABP, PK-PD target attainment analyses were undertaken.

Methods: Using parameter estimates from a population PK model [3‑compartments; mixed linear plus saturable elimination; 2 parallel first-order absorption processes; creatinine clearance (CLcr) was a predictor of clearance], free-drug plasma concentration-time profiles were generated for 5,000 simulated patients with varying CLcr following delafloxacin 300 mg IV q12h for 3 days followed by 450 mg PO q12h for 2 days. AUC0‑24 on Days 1 and 4 were calculated. Percent probabilities of PK‑PD target attainment by MIC and overall (i.e., weighted over the MIC distributions for SP and SA isolates from USA and Europe) were determined using median free-drug plasma AUC:MIC ratio targets associated with 1‑ and 2-log10 CFU reductions from baseline from a neutropenic lung infection model for SP (3.36 and 24.5, respectively) and SA (7.92 and 36.2, respectively). The results were stratified by renal function group [normal (CLcr ≥90 mL/min/1.73 m2) and mild (CLcr 60 to 89 mL/min/1.73 m2) or moderate (CLcr 30 to 59 mL/min/1.73 m2) renal impairment].

Results: Percent probabilities of attaining free-drug plasma AUC:MIC ratio targets associated with a 1-log10 CFU reduction from baseline by MIC on Day 1 by renal group for SP (Figure 1) and SA (Figure 2) were similar to those on Day 4. Percent probabilities of PK-PD target attainment on either day across renal groups were ≥99.5% for SP at a MIC value of 1 mg/L and ≥96.3% for SA at a MIC value of 0.5 mg/L. Overall percent probabilities of PK-PD target attainment were ≥93.3%. For free-drug plasma AUC:MIC ratio targets associated with a 2-log10CFU reduction from baseline, percent probabilities of PK-PD target attainment at a MIC value of 0.12 mg/L on either Days 1 or 4 were ≥99.8 and ≥93.7% for SP and SA, respectively.

Conclusion: These data provide support for delafloxacin 300 mg IV q12h for 3 days followed by 450 mg PO q12h for 2 days to treat patients with CABP who have normal renal function or mild or moderate renal impairment.


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, Alexander J. Lepak, M.D.2, David R. Andes, M.D., FIDSA2, Robert K. Flamm, Ph.D.3, Sue K. Cammarata, M.D.4 and Paul G. Ambrose, Pharm.D., FIDSA1, (1)Institute for Clinical Pharmacodynamics, Schenectady, NY, (2)University of Wisconsin School of Medicine and Public Health, Madison, WI, (3)JMI Laboratories, Inc., North Liberty, IA, (4)Melinta Therapeutics, Inc., New Haven, CT

Disclosures:

S. Bhavnani, Melinta Therapeutics Inc.: Research Contractor , Research support

L. Zhang, Melinta Therapeutics Inc.: Research Contractor , Research support

C. M. Rubino, Melinta Therapeutics Inc.: Research Contractor , Research support

J. C. Bader, Melinta Therapeutics Inc.: Research Contractor , Research support

A. J. Lepak, Melinta Therapeutics Inc.: Research Contractor , Research support

D. R. Andes, Melinta Therapeutics Inc.: Research Contractor , Research support

R. K. Flamm, Melinta Therapeutics Inc.: Research Contractor , Research support

S. K. Cammarata, Melinta Therapeutics Inc.: Employee , Salary

P. G. Ambrose, Melinta Therapeutics Inc.: Research Contractor , Research support

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