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.
S. M. Bhavnani,
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
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