1324 - Target Attainment of Exebacase, a First-In-Class Antibacterial Lysin, to Determine Optimal Doses for Adult Patients with Staphylococcus aureus (S. aureus) Bloodstream Infections (Bacteremia) Including Endocarditis

Background: Exebacase, a novel, antibacterial direct lytic agent for the treatment of S. aureus bacterimia and endocarditis, studied in Phase 1 and 2 trials, demonstrated potential to improve clinical outcomes when used in addition to conventional antibiotics. Objectives were to develop population PK (PPK) model and perform target attainment (TA) simulations to determine optimal clinical doses.

Methods: PPK model was developed with data from 72 patients receiving Exebacase, in addition to the standard of care, as single 2-hr infusion of 0.25 mg/kg (0.12 mg/kg for patients with creatinine clearance (CrCL) < 60 mL/min). PPK model was used for TA simulations of various IV regimens.

Results: 3-compartment model best fit the data, parameters were well estimated (CL=4.2 L/hr (RSE=5.5%), Vc=4.5 L (RSE=8.2%)).  Total volume of distribution (V_d) was 20.2 L. Values were lower than estimated previously in healthy subjects, CL=7.1 L/hr and V_d=27.7 L. CrCL was the only clinically meaningful covariate. Patients with moderate and severe renal impairment are expected to have 1.3 to 2-fold higher AUC_0-24 or C_max than patients with normal renal function.  Age was statistically significant on peripheral clearance but was not clinically meaningful (≤4% effect on exposure).
TA simulations were stratified by renal function across a range of fixed as well as weight-based doses (all simulated as 2-hr infusion).  In patients with normal renal function or mild impairment, 18 mg dose result in C_max and AUC_0-24 of 1254 ng/mL and 3026 ng*hr/mL, respectively. In patients with moderate or severe renal impairment, 12 mg dose result in C_max and AUC_0-24 of 1107 ng/mL and 3099 ng*hr/mL, respectively.  In ESRD patients including  hemodialysis, 8 mg dose result in C_max and AUC_0-24 of 910 ng/mL and 3109 ng*hr/mL, respectively. These exposures place >99% subjects above efficacious thresholds of AUC/MIC >0.2 established in animals.

Conclusion: PPK model described exebacase PK in patients adequately. CL and V_d were estimated to be 40% and 17% lower, respectively, than healthy subjects. CrCL was the only clinically meaningful covariate requiring dose adjustment. TA assessments identified doses that achieve minimum efficacy target (AUC/MIC≥0.2) in >99% of patients with S. aureus. Based on these simulations, fixed dosing schedule was recommended.