Methods: Human PK prediction of ETX2514 was completed using single species allometry for volume of distribution (Vdss) from dog PK, while rat and dog allometry was utilized to predict non-renal clearance (CLmetab). Renal excretion of unchanged drug was found to be a significant route of elimination. Human renal clearance (CLrenal) was predicted using dog-human renal correlation. Half-life was calculated as ln2*Vdss/CLtotal. Variance in Phase 1 PK data for avibactam was applied to the prediction of ETX2514 and combined with Phase 2 SUL human PK in support of probability of target attainment (pTA) analysis to meet PK/PD exposure targets. MIC distribution of a contemporary panel of clinical A. baumannii isolates was used to determine cumulative fraction of response (CFR). A clinical dose regimen predicted to exceed >90% pTA and CFR was considered as criteria for success.
Results: Allometric scaling predicts human Vdss of 0.26 L/kg (range: 0.22-0.31) and CLTotal of 3.1 mL/min/kg (range 2.4-4.0) suggesting a half-life of 1.1 hr. Urinary excretion of >90% of unchanged drug was projected based upon dog-human renal correlation. These predicted PK properties are consistent with those of SUL, enabling use of the combination in the same dose regimen. Accounting for projected PK variability of ETX2514 and SUL, the current clinical dose of SUL at 4 gm/day combined with 2 gm/day of ETX2514 is expected to deliver >90% CFR when administered as 3 hr infusions of 0.5 gm ETX2514/1.0 gm SUL q6hr.
Conclusion: Human PK predictions of ETX02514 suggest good compatibility for use in combination with SUL for the treatment of A. baumannii infections. A clinical regimen of 0.5 gm ETX2514/1.0 gm SUL q6h infused over 3 hr is anticipated to have >90% pTA and >90% CFR.
J. Mueller, Entasis Therapeutics: Employee and Shareholder , Salary
R. Tommasi, Entasis Therapeutics: Employee , Salary
Entasis Therapeutics: Employee , Salary
H. Shankaran, None
D. Ferguson, None