Abstract
Background
Xeruborbactam (XERU) is a member of a new class of cyclic boronic acid β-lactamase inhibitors with inhibitory activity against major members of Class A, B, C, and D beta-lactamases. This report describes the safety and pharmacokinetics of XERU following multiple doses alone and in combination with meropenem.
Methods
Twenty-four healthy subjects were enrolled into one of 3 cohorts with XERU alone. XERU was administered as a 500 mg loading dose followed by 250 mg q8h or 1000 mg loading dose followed by 500 mg q8h. 15 healthy subjects were enrolled in a single cohort of meropenem alone administered as a 4000 mg loading dose followed by 2000 mg q8h or meropenem in combination with XERU administered as a 500 mg loading dose followed by 250 mg q8h for 10 days. Intensive plasma sampling was obtained after dosing and assayed for drug content using validated LC-MS/MS methods.
Results
XERU and Meropenem Steady State pharmacokinetic parameters are shown in the table below.
| Parameter | XERU alone | XERU alone | XERU (Combo) |
|---|---|---|---|
| 250 mg q8h | 500 mg q8h | 250 mg q8h | |
| (N=5) | (N=6) | (N=9) | |
| Cmax (mg/L) | 69.0 ± 7.5 | 99.9 ± 9.7 | 60.7 ± 15.1 |
| AUC0-tau (mg·h/L) | 472.1 ± 45.4 | 649.6 ± 44.4 | 388.4 ± 39.7 |
| Clearance (L/h) | 0.53 ± 0.06 | 0.77 ± 0.06 | 0.65 ± 0.07 |
| Vss (L) | 15.5 ± 2.6 | 17.8 ± 2.0 | 18.2 ± 1.9 |
| Half-Life (h) | 31.0 ± 1.5 | 24.9 ± 1.8 | 30.1 ± 4.9 |
No subjects discontinued due to AEs and no SAEs were observed. There was no evidence of increasing numbers or severity of AEs with increasing dose. All AEs were mild or moderate in severity.
Conclusion
XERU was safe and well-tolerated when administered alone and in combination with meropenem. XERU has unique PK properties that includes a long elimination half-life that provides sustained plasma concentrations. The loading dose of XERU allows for rapid achievement of steady state plasma levels of XERU within the first day of treatment. XERU plasma PK properties, along with a broad spectrum of inhibitory activity, facilitates its use with multiple beta-lactam antibiotics including meropenem.
Disclosures
David Griffith, n/a, Qpex Biopharma: Employee Jason Roberts, BPharm(Hons), PhD, FSHP, FISAC, British Society of Chemotherapy: Grant/Research Support|Cipla: Honoraria|Gilead: Advisor/Consultant|MSD: Advisor/Consultant|MSD: Honoraria|Pfizer: Board Member|Pfizer: Honoraria|Qpex: Grant/Research Support|Sandoz: Board Member|Summit: Advisor/Consultant|Wolters Kluwer: Advisor/Consultant Elizabeth Morgan, n/a, Qpex Biopharma: Employee Shawnee Gehrke, n/a, Qpex Biopharma: Employee Michael Dudley, n/a, ArrePath: Board Member|Qpex Biopharma: Board Member|Qpex Biopharma: Employee Jeff Loutit, MBChB, Qpex Biopharma: Employee.