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)

Abstract

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. 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/minute/1.73 m2) or mild (60≤CLcr < 90 mL/minute/1.73 m2), moderate (30 ≤ CLcr < 60 mL/minute/1.73 m2), or severe renal impairment (15 ≤ CLcr < 30 mL/minute/1.73 m2) or with end stage renal disease (ESRD; 5 ≤ CLcr < 15 mL/minute/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]. 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%. These data provide dose support for delafloxacin to treat patients with ABSSSI and normal renal function or renal impairment. 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