1851. Population Pharmacokinetic (PPK) and Pharmacokinetic-Pharmacodynamic (PK-PD) Target Attainment Analyses for Delafloxacin to Support Dose Selection for the Treatment of Patients with Acute Bacterial Skin and Skin Structure Infections (ABSSSI)
Session: Poster Abstract Session: Clinical Study with New Antibiotics and Antifungals
Saturday, October 7, 2017
Room: Poster Hall CD

Background: Delafloxacin is a novel fluoroquinolone with activity against pathogens associated with ABSSSI, including methicillin-susceptible and ‑resistant S. aureus (SA). To provide support for an IV to PO dosing regimen to treat patients with ABSSSI, PPK and PK-PD target attainment analyses were undertaken.

Methods: PPK models were fit to PK data for IV delafloxacin from 4 Phase 1, 1 Phase 2, and 2 Phase 3 studies. To assess PK-PD target attainment, the following simulated patient populations varying by creatinine clearance (CLcr) were generated: normal renal function (90≤CLcr<200 mL/min/1.73 m2) or mild (60≤CLcr<90 mL/min/1.73 m2), moderate (30≤CLcr<60 mL/min/1.73 m2), or severe renal impairment (15≤CLcr<30 mL/min/1.73 m2) or with end stage renal disease (ESRD; 5≤CLcr<15 mL/min/1.73 m2) receiving or not receiving hemodialysis. Using the PPK model and CLcr, individual post-hoc parameter estimates, enriched with simulated bioavailability (F) based on a prior distribution [Zhang L. et al.  IDWeek 2016, P1972], were generated and used with a protein binding estimate (84%) to calculate Day 1 and 4 free-drug AUC. Simulated patients received delafloxacin 300 mg IV q12h on Days 1-3 followed by 450 mg PO q12h on Day 4 or for those with severe renal impairment or ESRD, 200 mg IV q12h on Days 1-3 followed by 450 mg PO q12h on Day 4. Percent probabilities of PK‑PD target attainment by MIC and overall (i.e., weighted over SA MIC distributions) were determined using median free-drug AUC:MIC ratio targets associated with net bacterial stasis and a 1‑log10 CFU reduction from baseline from a neutropenic murine-thigh infection model (9.3 and 14.3, respectively) [Burak et al., ICAAC 2009; A1-1941].

Results:  Delafloxacin PK were best described by a 3-compartment model with mixed linear and nonlinear clearance. Percent probabilities of PK-PD target attainment by MIC on Days 1 and 4 were similar across renal groups (Table 1). At the MIC90 of 0.25 µg/mL for SA, percent probabilities of attaining a free-drug AUC:MIC ratio associated with net bacterial stasis on either Days 1 or 4 were ≥ 99.5%. Overall percent probabilities ranged from 91.9 to 99.8%.

Conclusion: These data provide dose support for delafloxacin to treat patients with ABSSSI and normal renal function or renal impairment.


 

Sujata M. Bhavnani, Pharm.D., M.S.1, Li Zhang, M.D., Ph.D.1, Paul G. Ambrose, Pharm.D., FIDSA1, Robert K. Flamm, PhD2, Sue K. Cammarata, MD3 and Christopher M. Rubino, Pharm.D.1, (1)ICPD, Schenectady, NY, (2)United States Committee on Antimicrobial Susceptibility Testing, Silverton, OR, (3)Melinta Therapeutics, Inc., New Haven, CT

Disclosures:

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

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

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

R. K. Flamm, Melinta Therapeutics: Research Contractor , Research grant

S. K. Cammarata, Melinta Therapeutics: Employee and Shareholder , Salary

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

Findings in the abstracts are embargoed until 12:01 a.m. PDT, Wednesday Oct. 4th with the exception of research findings presented at the IDWeek press conferences.